Catheter or guidewire device including flow sensing and use thereof

ABSTRACT

Devices and methods are provided for performing procedure on tissue with flow monitoring using flow sensors. The devices include an elongated member, and at least one flow sensor disposed on the elongated member. The flow sensor includes at least one temperature sensor and at least one heating element having a cavity. At least a portion of the at least one temperature sensor is housed in the cavity. A temperature measurement of the temperature sensor provides an indication of the flow rate of a fluid proximate to the flow sensor.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.14/147,347, entitled “CATHETER OR GUIDEWIRE DEVICE INCLUDING FLOWSENSING AND USE THEREOF,” filed on Jan. 3, 2014, now U.S. Pat. No.9,295,842, which is a continuation-in-part of U.S. patent applicationSer. No. 13/844,677, entitled “CATHETER DEVICE INCLUDING FLOW SENSING,”filed on Mar. 15, 2013, now U.S. Pat. No. 9,168,094, which claims thebenefit of U.S. provisional application Ser. No. 61/668,338, filed onJul. 5, 2012, entitled “METHOD AND APPARATUS FOR DENERVATION,” U.S.provisional application Ser. No. 61/728,653, filed on Nov. 20, 2012,entitled “RENAL DENERVATION,” and U.S. provisional application Ser. No.61/733,575, filed on Dec. 5, 2012, entitled “INCREASING THE RESOLUTIONOF TEMPERATURE MEASUREMENT FOR FLOW DETECTION IN THE RENAL ARTERY,” eachof which is hereby incorporated herein by reference in its entirety,including drawings.

BACKGROUND

Diseases such as heart disease, stroke and hypertension are globalepidemics that affect billions of people worldwide. Hypertensionunderlies the progression of several debilitating diseases, includingheart disease and stroke. Despite widespread use of anti-hypertensionmedication to counter high blood pressure, the prevalence ofhypertension is alarmingly high and constitutes a severe economic burdenon health care.

Blood pressure is controlled, in large part, by the sympathetic nervoussystem. The sympathetic nervous system involves several organs that areresponsible for regulating blood pressure such as the brain, heart andkidneys. The kidney is a key element in long-term blood pressureregulation. Hypertension, or high blood pressure, results fromhyperactive renal nerves. This, in turn, can cause heart, kidney, andblood vessel damage.

Other systems of the body where nerves activity can affect fluid flowinclude the carotid sinus, the carotid body, the vagal nerve, thepulmonary artery, the celiac ganglion, and the bladder trigone.

SUMMARY

The Inventors have recognized that an ability to monitor proceduresduring treatment of tissue is advantageous. For example, renal ablationrepresents a useful and potentially safe technique. Its applicabilitymay be limited due to a lack of sensing capability following a proceduresuch as ablation.

In view of the foregoing, various examples described herein are directedgenerally to systems, apparatus and methods for facilitating themonitoring and/or verification of the outcome of procedures, such as butnot limited to a nerve denervation and/or a nerve pacing procedure. Theresult of the monitoring and/or verification can be used to determine aclinical endpoint of a denervation and/or a pacing procedure. Systemsand methods described herein also facilitate establishing a credibleendpoint in denervation procedures, including renal sympatheticdenervation procedures.

Systems and methods described herein provide novel devices, includingcatheter devices or guidewire devices, with diagnostic capabilities, toassess the state of the tissue following each procedure, including eachablation cycle of a series of ablation cycles.

Systems and methods described herein provide novel devices, includingcatheter devices, with diagnostic capabilities, to assess the state ofthe tissue in other systems, including in pulmonary veins, coronaryarteries, and peripheral blood vessels, following each procedure in aseries of procedures, such as but not limited to each ablation cycle ofa series of ablation cycles.

In an example, a system, apparatus and method herein provide noveldevices that can be implemented for measuring blood flow, or other fluidflow, coupled with pacing and/or denervation of nerves, using a singlesmart catheter or guidewire device.

In an example, a system, apparatus and method herein can be implementedfor facilitating monitoring and/or verifying the outcome of denervationand/or pacing procedures performed in one or more systems, such as butnot limited to the carotid sinus, the carotid body, the vagal nerve, thepulmonary artery, celiac ganglion, the bladder trigone, or the renalarteries.

In an example, a system, apparatus and method is provided that is basedon thin device islands, including integrated circuitry (IC) chips and/orstretchable and/or flexible interconnects that are encapsulated in anencapsulant.

In an example, a system, apparatus and method herein can be implementedfor performing a procedure on the portion of tissue, and where theprocedure is a denervation procedure or a nerve stimulation procedure.In an example, the procedure can be a carotid sinus denervation, acarotid body disruption, a vagus nerve stimulation, a pulmonary arterydenervation, a celiac ganglion disruption, a bladder trigone ablation,or a renal denervation.

In an example, a system, apparatus and method is provided fordetermining a flow rate of a fluid proximate to a portion of a tissue.An example device according to this principle includes an elongatedmember having a proximal portion and a distal portion, and a flow sensordisposed proximate to the distal portion of the elongated member. Theflow sensor includes at least one temperature sensor and at least oneheating element to heat an area proximate to the elongated member, atleast a portion of the at least one heating element forming a cavity. Atleast a portion of the at least one temperature sensor is housed in aportion of the cavity. A temperature measurement of the temperaturesensor provides a first indication of a flow rate of the fluid proximateto the flow sensor.

In an example, the device can further include an inflatable and/orexpandable body coupled to a portion of the elongated member and havinga proximal portion and a distal portion. The distal portion of theinflatable and/or expandable body is disposed proximate to the flowsensor. The example device can further include an electronic circuitcoupled with the inflatable and/or expandable body, where the electroniccircuit comprises at least one stretchable interconnect, and where theelectronic circuit is stretchable and conformable such that theelectronic circuit accommodates an expansion of the inflatable and/orexpandable body. The electronic circuit can further include at least onepassive electronic component and/or at least one active electroniccomponent, and wherein the at least one stretchable interconnectelectrically couples at least two electronic components of theelectronic circuit.

In an example, the device can include at least one heating element iscomprised of a coiled resistive wire, where a hollow portion of thecoiled resistive wire forms the cavity. In another example, the at leastone heating element can include a thin-film patterned resistive element,where the at least one heating element is formed in a substantiallycylindrical conformation including the cavity. In another example, thethin-film patterned resistive element can include a pattern of resistiveelements disposed on a stretchable and/or flexible substrate. Theresistive elements may be formed in a linear pattern, a serpentinepattern, a boustrophedonic pattern, a zig-zag pattern, a wavy pattern, apolygonal pattern, or a substantially circular pattern.

In an example, a system, apparatus and method herein is provided fordisplaying representations of parameters of an inflatable body and/orexpandable body disposed proximate to a portion of a tissue. In anexample, the inflatable body and/or expandable body includes a pluralityof sensors coupled to at least a portion of the inflatable body and/orexpandable body. An example apparatus can include a user interface, atleast one memory to store processor-executable instructions, and atleast one processing unit communicatively coupled to the at least onememory. Upon execution of the processor-executable instructions, the atleast one processing unit can controls the user interface to display atleast one representation of the parameters. The at least onerepresentation includes: (A) a first representation of a state of theinflatable body and/or expandable body and (B) a second representationof a state of at least one sensor of the plurality of sensors. The firstrepresentation can include (i) a first form indicator to indicate thatthe inflatable body and/or expandable body is in an inflated and/or anexpanded state, or (ii) a second form indicator to indicate that theinflatable body and/or expandable body is in a deflated and/or acollapsed state. The second representation can include (i) a firstactivation indicator to indicate that the at least one sensor of theplurality of sensors measures a signal below a threshold value, or (ii)a second activation indicator to indicate that the at least one sensorof the plurality of sensors measures a signal above or about equal tothe threshold value.

In an example implementation of the apparatus, a signal below aspecified (threshold) value indicates that the at least one sensor isnot in contact with a portion of the tissue, and a signal above or aboutequal to the specified (threshold) value indicates that the at least onesensor is in contact with a portion of the tissue.

In an example implementation of the apparatus, the first activationindicator and the second activation indicator can be displayed as binaryvisual representations and/or as quantitative visual representationsthat correspond to a magnitude of the signal.

In an example implementation of the apparatus, the at least oneprocessing unit can be used to control the user interface to causedisplay of the first representation and the second representation in astaged process, such that no second representation is displayed whilethe first representation is the first form indicator, and the secondrepresentation is displayed once the first representation is the secondform indicator.

In an example implementation of the apparatus, the at least oneprocessing unit can be used to control the user interface to furthercause display of an indication of at least one stage of a procedurebeing performed on the portion of the tissue and/or an indication of anendpoint of a procedure being performed on the portion of the tissue.

In an example, a system, apparatus and method herein can be implementedfor performing a medical treatment procedure. An example method caninclude disposing in proximity to the tissue an apparatus that includesan elongated member having a proximal portion and a distal portion, atleast one flow sensor disposed proximate to the distal portion of theelongated member, and a reference temperature sensor disposed on aproximal portion of the elongated member. Each of the at least one flowsensor includes at least one temperature sensor, and at least oneheating element disposed proximate to the at least one temperaturesensor. The example apparatus can include a control module coupled tothe at least one flow sensor and the reference temperature sensor. Theexample method includes using the control module to maintain atemperature difference between the reference temperature sensor and thetemperature sensor of the at least one flow sensor at a stage ofperformance of the medical treatment procedure. Use of the examplecontrol module includes monitoring a value of a temperature measurementof the reference temperature sensor and/or a temperature measurement ofthe temperature sensor of the at least one flow sensor, and controllinga first signal to the at least one heating element to cause the at leastone heating element to emit heat or discontinue emitting heat, such thatthat the temperature difference is maintained.

In an example implementation of the method, the temperature differencecan be a constant temperature difference or a time-varying temperaturedifference. In an example the temperature difference can be a constanttemperature difference, where the constant temperature difference isabout 1.5° C., about 2.0° C., about 2.5° C., about 3.0° C., about 3.5°C., about 4.0° C., or about 4.5° C.

In an example implementation, the example control module includes aproportional-integral-derivative (PID) controller or an anemometer.Where the control module includes a PID controller, the method canfurther include applying the PID controller to compare the value of thetemperature measurement of the reference temperature sensor to thetemperature measurement of the temperature sensor of at least one flowsensor, and to determine a second signal based on the comparison, andusing the control module to determine the first signal to the at leastone heating element based on the second signal.

In an example implementation of the method, stages of the method can berepeated until the difference falls in a specified range of values.

In an example, a system, apparatus and method herein can be implementedfor monitoring a hemodynamic effect during a medical treatment procedureperformed on a vascular tissue. An example method can include disposingin proximity to the tissue an apparatus that includes an elongatedmember having a proximal portion and a distal portion, at least one flowsensor disposed proximate to the distal portion of the elongated member,and at least one component coupled to the elongated member to perform amedical treatment procedure on a portion of the tissue proximate to theelongated member. The example method can further include activating theat least one component to perform the medical treatment procedure on theportion of the tissue, administering a substance that causes a change indimension of the vascular tissue, using the at least one flow sensor toperform at least one flow measurement, the at least one flow measurementproviding data indicative of a change in the flow subsequent to themedical treatment procedure of a fluid proximate to the apparatus, andanalyzing the data indicative of the flow of the fluid to determine atleast one parameter indicative of the change in the hemodynamics of thefluid. A reduction in the change in the hemodynamics of the fluid isused to provide an indication of the efficacy of the medical treatmentprocedure.

In an example implementation of the method, stages of the method can berepeated until the rate of reduction of the change in the hemodynamicsof the fluid falls below a specified value. The example method canfurther include generating an indication of an endpoint of the medicaltreatment procedure when the rate of reduction of the change in thehemodynamics of the fluid falls below the specified value.

In an example implementation of the method, the substance can include anendogenous substance or an exogenous substance. For example, thesubstance can include a dopamine, adenosine, prostacyclin, saline, ornitric oxide. The at least one component can be an ablative component,where the medical treatment procedure is a denervation procedure.

An example system, apparatus and method herein provides a catheter orguidewire device for performing a procedure on tissue. The catheter orguidewire device includes an inflatable and/or expandable body disposednear a distal end of the catheter, at least one flow sensor disposed onthe inflatable and/or expandable body. At least one component is coupledto the catheter or guidewire to perform an ablation procedure on aportion of the tissue of the renal artery. Each of the at least one flowsensors includes a heating element to heat an area proximate to theinflatable and/or expandable body, the heating element including acavity, and a temperature sensor at least partially disposed in thecavity of the heating element. Measurement of the temperature sensorprovides an indication of a flow rate of a fluid proximate to theinflatable and/or expandable body.

The following publications, patents, and patent applications are herebyincorporated herein by reference in their entirety:

-   Kim et al., “Stretchable and Foldable Silicon Integrated Circuits,”    Science Express, Mar. 27, 2008, 10.1126/science.1154367;-   Ko et al., “A Hemispherical Electronic Eye Camera Based on    Compressible Silicon Optoelectronics,” Nature, Aug. 7, 2008, vol.    454, pp. 748-753;-   Kim et al., “Complementary Metal Oxide Silicon Integrated Circuits    Incorporating Monolithically Integrated Stretchable Wavy    Interconnects,” Applied Physics Letters, Jul. 31, 2008, vol. 93,    044102;-   Kim et al., “Materials and Noncoplanar Mesh Designs for Integrated    Circuits with Linear Elastic Responses to Extreme Mechanical    Deformations,” PNAS, Dec. 2, 2008, vol. 105, no. 48, pp.    18675-18680;-   Meitl et al., “Transfer Printing by Kinetic Control of Adhesion to    an Elastomeric Stamp,” Nature Materials, January, 2006, vol. 5, pp.    33-38;-   U.S. Patent Application publication no. 2010 0002402-A1, published    Jan. 7, 2010, filed. Mar. 5, 2009, and entitled “STRETCHABLE AND    FOLDABLE ELECTRONIC DEVICES;”-   U.S. Patent Application publication no. 2010 0087782-A1, published    Apr. 8, 2010, filed Oct. 7, 2009, and entitled “CATHETER BALLOON    HAVING STRETCHABLE INTEGRATED CIRCUITRY AND SENSOR ARRAY;”-   U.S. Patent Application publication no. 2010 0116526-A1, published    May 13, 2010, filed Nov. 12, 2009, and entitled “EXTREMELY    STRETCHABLE ELECTRONICS;”-   U.S. Patent Application publication no. 2010 0178722-A1, published    Jul. 15, 2010, filed Jan. 12, 2010, and entitled “METHODS AND    APPLICATIONS OF NON-PLANAR IMAGING ARRAYS;” and-   U.S. Patent Application publication no. 2010 027119-A1, published    Oct. 28, 2010, filed Nov. 24, 2009, and entitled “SYSTEMS, DEVICES,    AND METHODS UTILIZING STRETCHABLE ELECTRONICS TO MEASURE TIRE OR    ROAD SURFACE CONDITIONS.”-   Kim, D. H. et al. (2010). Dissolvable films of silk fibroin for    ultrathin conformal bio-integrated electronics. Nature Materials, 9,    511-517.-   Omenetto, F. G. and D. L. Kaplan. (2008). A new route for silk.    Nature Photonics, 2, 641-643.-   Omenetto, F. G., Kaplan, D. L. (2010). New opportunities for an    ancient material. Science, 329, 528-531.-   Halsed, W. S. (1913). Ligature and suture material. Journal of the    American Medical Association, 60, 1119-1126.-   Masuhiro, T., Yoko, G., Masaobu, N., et al. (1994). Structural    changes of silk fibroin membranes induced by immersion in methanol    aqueous solutions. Journal of Polymer Science, 5, 961-968.-   Lawrence, B. D., Cronin-Golomb, M., Georgakoudi, I., et al. (2008).    Bioactive silk protein biomaterial systems for optical devices.    Biomacromolecules, 9, 1214-1220.-   Demura, M., Asakura, T. (1989). Immobilization of glucose oxidase    with Bombyx mori silk fibroin by only stretching treatment and its    application to glucose sensor. Biotechnololgy and Bioengineering,    33, 598-603.-   Wang, X., Zhang, X., Castellot, J. et al. (2008). Controlled release    from multilayer silk biomaterial coatings to modulate vascular cell    responses. Biomaterials, 29, 894-903.-   U.S. patent application Ser. No. 12/723,475 entitled “SYSTEMS,    METHODS, AND DEVICES FOR SENSING AND TREATMENT HAVING STRETCHABLE    INTEGRATED CIRCUITRY,” filed Mar. 12, 2010.-   U.S. patent application Ser. No. 12/686,076 entitled “Methods and    Applications of Non-Planar Imaging Arrays,” filed Jan. 12, 2010.-   U.S. patent application Ser. No. 12/636,071 entitled “Systems,    Methods, and Devices Using Stretchable or Flexible Electronics for    Medical Applications,” filed Dec. 11, 2009.-   U.S. Patent Application publication no 2012-0065937-A1, published    Mar. 15, 2012, and entitled “METHODS AND APPARATUS FOR MEASURING    TECHNICAL PARAMETERS OF EQUIPMENT, TOOLS AND COMPONENTS VIA    CONFORMAL ELECTRONICS.”-   U.S. patent application Ser. No. 12/616,922 entitled “Extremely    Stretchable Electronics,” filed Nov. 12, 2009.-   U.S. patent application Ser. No. 12/575,008 entitled “Catheter    Balloon Having Stretchable Integrated Circuitry and Sensor Array,”    filed on Oct. 7, 2009.-   U.S. patent application Ser. No. 13/336,518 entitled “Systems,    Methods, and Devices Having Stretchable Integrated Circuitry for    Sensing and Delivering Therapy,” filed Dec. 23, 2011.

It should be appreciated that all combinations of the foregoing conceptsand additional concepts described in greater detail below (provided suchconcepts are not mutually inconsistent) are contemplated as being partof the inventive subject matter disclosed herein. It also should beappreciated that terminology explicitly employed herein that also mayappear in any disclosure incorporated by reference should be accorded ameaning most consistent with the particular concepts disclosed herein.

BRIEF DESCRIPTION OF THE DRAWINGS

The skilled artisan will understand that the figures, described herein,are for illustration purposes only, and that the drawings are notintended to limit the scope of the disclosed teachings in any way. Insome instances, various aspects or features may be shown exaggerated orenlarged to facilitate an understanding of the inventive conceptsdisclosed herein (the drawings are not necessarily to scale, emphasisinstead being placed upon illustrating the principles of the teachings).In the drawings, like reference characters generally refer to likefeatures, functionally similar and/or structurally similar elementsthroughout the various figures.

FIGS. 1A-1C show example voltage waveforms for stimulating nerves,according to the principles described herein.

FIG. 2 shows a plot of percent changes of renal blood flow as a functionof integrated voltage being delivered during pacing, according to theprinciples described herein.

FIG. 3A shows an example device that can be used to perform a procedure,according to the principles described herein.

FIG. 3B shows an example flow sensor, according to the principlesdescribed herein.

FIGS. 4A and 4B show example implementation of an example device,according to the principles described herein.

FIG. 5 shows an example implementation of an electronic circuit and flowsensor, according to the principles described herein.

FIGS. 6A-6D show example flow sensors or example heating elements,according to the principles described herein,

FIG. 7A shows another example device, according to the principlesdescribed herein.

FIG. 7B shows another example device, according to the principlesdescribed herein.

FIGS. 8A and 8B illustrate an operation of the example flow sensors ofFIG. 7A-7B, according to the principles described herein.

FIG. 9 shows an example simplified schematic of a differentialpre-amplifier, according to the principles described herein.

FIG. 10 shows an example operation of a 3-ω acquisition system,according to the principles described herein.

FIG. 11 illustrates an operation of an example flow sensor, according tothe principles described herein.

FIG. 12 shows an example block diagram of an example PID controllercoupled to an example flow sensor, according to the principles describedherein.

FIG. 13 shows an example of synchronous demodulation, according to theprinciples described herein.

FIGS. 14A-14C show cross-sectional layering structure of variouscomponents of an example device, according to the principles describedherein.

FIG. 15 shows a flowchart of an example method for performing an exampleassessment, according to the principles described herein.

FIG. 16 shows example plots of flow measurements, according to theprinciples described herein.

FIG. 17 shows a block diagram of an example system including anassessment module according to the principles described herein.

FIG. 18A shows an example flow sensor, according to the principlesdescribed herein.

FIG. 18B shows example measurements using an example flow sensor,according to the principles described herein.

FIG. 19 shows an example method for performing a procedure, according tothe principles described herein.

FIG. 20 shows an example architecture of an illustrative computersystem, according to the principles described herein

FIGS. 21A and 21B show the results of example measurement using anexample device, according to the principles described herein.

FIGS. 22A and 22B show the results of example use of an example device,according to the principles described herein

FIGS. 23A-23G illustrates examples of multi-electrode and ballooncatheter devices, according to the principles described herein.

FIGS. 24A-24D shows examples of catheter devices.

FIGS. 24E and 24F shows example forms of sensing, according to theprinciples described herein.

FIG. 25 shows a non-limiting example of flow sensors on catheters,according to the principles described herein.

FIG. 26 shows an example of flow sensors on a spiral-shaped catheter,according to the principles described herein.

FIG. 27 shows a catheter with bipolar electrodes and metalinterconnects, according to the principles described herein.

FIG. 28A-28D shows example displays of data or analysis, according tothe principles described herein.

FIG. 29 shows example displays of data and plots, according to theprinciples described herein.

DETAILED DESCRIPTION

Following below are more detailed descriptions of various conceptsrelated to, and embodiments of, an apparatus and systems for embeddingthinned chips in a flexible polymer. It should be appreciated thatvarious concepts introduced above and described in greater detail belowmay be implemented in any of numerous ways, as the disclosed conceptsare not limited to any particular manner of implementation. Examples ofspecific implementations and applications are provided primarily forillustrative purposes.

As used herein, the term “includes” means includes but is not limitedto, the term “including” means including but not limited to. The term“based on” means based at least in part on. As used herein, the term“disposed on” or “disposed above” is defined to encompass “at leastpartially embedded in.”

With respect to substrates or other surfaces described herein inconnection with various examples of the principles herein, anyreferences to “top” surface and “bottom” surface are used primarily toindicate relative position, alignment and/or orientation of variouselements/components with respect to the substrate and each other, andthese terms do not necessarily indicate any particular frame ofreference (e.g., a gravitational frame of reference). Thus, reference toa “bottom” of a substrate or a layer does not necessarily require thatthe indicated surface or layer be facing a ground surface. Similarly,terms such as “over,” “under,” “above,” “beneath” and the like do notnecessarily indicate any particular frame of reference, such as agravitational frame of reference, but rather are used primarily toindicate relative position, alignment and/or orientation of variouselements/components with respect to the substrate (or other surface) andeach other. The terms “disposed on” “disposed in” and “disposed over”encompass the meaning of “embedded in,” including “partially embeddedin.” In addition, reference to feature A being “disposed on,” “disposedbetween,” or “disposed over” feature B encompasses examples wherefeature A is in contact with feature B, as well as examples where otherlayers and/or other components are positioned between feature A andfeature B.

Renal denervation therapy can be used to disrupt the renal nerve throughablation, including through applying energy in the form of RF energy,heating, or cryo (extreme cold) to the nerves. This can be done byinserting a tube or catheter into the groin and guiding the device intothe renal artery. The renal denervation procedure ordinarily is notconfigured to provide measurement of the efficacy of the process.

Other non-limiting examples of ablation energy that can be applied usinga catheter with flow sensing according to the principles describedherein include radiofrequency (RF), ultrasound energy, cryoablation,drug-based ablation, alcohol injection, microwave energy ablation, andlight-based ablation (laser energy).

While the description of the assessment is described relative to aprocedure on a renal artery, the assessment of the efficacy of aprocedure can be performed in other systems. For example, an assessmentdescribed herein for determining the efficacy of a procedure using flowmeasurements can be applied to procedures being performed in othertissue lumen, such as pulmonary veins, coronary arteries, peripheralblood vessels, cardiac lumen, and any other lumen in which flow can beassessed.

Denervation therapy can be used to disrupt the nerve through ablation,including through applying energy in any of the forms described herein(such as applying RF energy, heating, or cryo (extreme cold) to thenerves), in other systems such as but not limited to the carotid sinus,the carotid body, the vagal nerve, the pulmonary artery, the celiacganglion, or the bladder trigone.

An increase in blood flow in the renal artery can be used as anindicator of the degree of efficacy of a renal sympathetic denervation(RSDN) procedure. For example, an indication of an increase in the rateof blood flow can be considered an indicator that a RSDN procedure iseffective in achieving the desired degree and/or amount of denervationin the tissue being targeted. Such an indication of the degree ofefficacy can be extrapolated to signal an endpoint to the procedure ifthe flow-rate of blood is approaching the desired level. As anotherexample, an indication of little or no change in the rate of blood flowcan be considered an indicator that a RSDN procedure is ineffective ormarginally effective in achieving the desired degree and/or amount ofdenervation in the tissue being targeted. Such an indication of thedegree of efficacy can be extrapolated used in a determination of anexpected number of additional procedures to be performed to achieve thedesired outcome, or potential changes that could be made to make theRSDN procedure more effective.

According to the principles described herein, example devices andmethods are described for determining the efficacy of a denervationprocedure, or a pacing or other stimulation procedure. Example methodsare disclosed that relate to monitoring changes in blood flow rates, orother fluid flow rates, before and/or after the denervation or pacing(or other stimulation) procedure to monitor the stage of the procedureor to determine an endpoint for performance of the procedure.

This disclosure relates to flow measurement systems that can beimplemented to determine the efficacy of interventional procedures,including denervation procedures such as but not limited to renaldenervation or pacing (or other stimulation) procedures. According to anexample and method described herein, a change in flow rate of bloodthrough the tissue lumen can be used to provide an indication of theeffectiveness of a procedure performed on the tissue (such as but notlimited to the renal artery). The procedure can be any procedure todisrupt the nerve, e.g., through ablation, including through applyingenergy in the form of RF energy, heating, or cryo (extreme cold) to thenerves. An example application of a flow measurement system, apparatusand method described herein is to provide an indication to a physicianthat the clinical procedure is successful.

According to the principles described herein, example devices andmethods are described for use in establishing a clinical endpoint in aprocedure in a renal artery or other tissue. In an example system andmethod, a measure of blood flow in a renal artery or other tissue priorto the procedure and/or subsequent to the procedure can be used toprovide an indication of an efficacy of a procedure. In another example,blood flow measurements during a pre-procedure cycle and/or during apost-procedure cycle can be used to establish a clinical endpoint forthe procedure being performed to disrupt the nerve, e.g., throughablation, including through applying energy in the form of RF energy,heating, or cryo (extreme cold) to the nerves.

Sympathetic nerve activity controls blood pressure and flow by virtue ofvasoconstriction. Delivery of electrical stimulation to sympatheticnerves can, in turn, be used to stimulate the nerves and cause amodulation in blood flow or other fluid flow. According to theprinciples described herein, example devices and methods are describedfor measuring changes in local blood flow and/or pressure during aprocedure, such as but not limited to a RSDN procedure.

At present, most forms of high-performance electronics and electrodesare rigid, bulky and have cylindrical cuff-like formats that areinherently low density and incompatible with the soft, complextopologies of arteries. In various example implementations, novelmultifunctional catheter devices are described that include novelmicrofabrication technology to build arrays of soft and flexiblenanomembrane flow sensing and electrode elements that can be used toprovide feedback about renal blood flow, while concurrently deliveringpacing energy and/or ablation energy. In various examples describedherein, novel design strategies and fabrication techniques are describedthat use inorganic semiconductor processes to achieve high performanceflexible flow sensor and electrode arrays on catheter devices, such asbut not limited to, spiral shaped and balloon catheters thatconcurrently measure flow and apply RF energy and pacing energy inside arenal artery.

An example catheter device according to the principles described hereincan include at least one pacing electrode. In a pacing procedure, apotential is applied to a portion of tissue proximate to a nerve tostimulate blood flow. FIGS. 1A-1C show example voltage waveforms thatcan be used to stimulate the nerves. FIG. 2 shows a plot of percentchanges of renal blood flow as a function of integrated voltage beingdelivered during pacing. FIGS. 1A-1C and FIG. 2 demonstrate that bloodflow can be changed in the renal artery due to programmed nervestimulation (during pacing). In an example, such pacing can be performedduring a procedure performed according to the principles describedherein. For example, at least one pacing electrode can be disposed on anexample catheter device described herein to provide an electricalstimulation to tissue, e.g., in a region of a nerve source, prior to,during, and/or following a procedure. That procedure can be anyprocedure that disrupts the renal nerve through ablation, includingthrough applying energy in the form of RF energy, heating, or cryo(extreme cold) to the nerves.

Example devices and methods are described that combine, on a singlecatheter device, components to perform a procedure on a tissue andcomponents to perform sensing of the flow rate of blood, according tothe principles described herein. Example devices and methods are alsodescribed that combine on a single catheter device, components toperform nerve stimulation (such as using pacing electrodes) andcomponents to perform sensing of the flow rate of blood, according tothe principles described herein. In an example, an indication of theflow rate of blood based on measurements using the catheter device canbe used to establish a clinical endpoint during a procedure, including aRSDN procedure.

FIG. 3A shows an example device 300 that can be used to perform aprocedure according to the principles described herein. The exampledevice 300 includes an inflatable and/or expandable body 302, a flowsensor 304 disposed on a portion of the inflatable and/or expandablebody 302, and an electronic circuit 306 disposed on the inflatableand/or expandable body 302. The electronic circuit 306 includes a numberof components that accommodate expanding of the inflatable and/orexpandable body 302. In FIG. 3A, the flow sensor 304 is illustrated asbeing disposed on a distal portion of the inflatable body. In anotherexample, the flow sensor can be disposed on or proximate to a proximalportion of the inflatable and/or expandable body.

In an example implementation, the flow sensor can be a formed asillustrated in FIG. 3B. FIG. 3B shows an example flow sensor 306′ thatincludes a heating element 307 disposed proximate to a temperaturesensor 308. The heating element 307 and temperature sensor 308 may bedisposed on, or encapsulated in, a support 309. Support 309 can beformed from a thermally conductive material. In various examples, theheating element 307 can be separated from the temperature sensor 308 bya separation “x”. The parameter “x” can be about 1 mm, about 2 mm, about3 mm, about 5 mm, about 8 mm, about 10 mm, about 12 mm, about 18 mm,about 24 mm, about 30 mm or more. Temperature sensor 308 can be athermocouple, a resistance temperature detector (RTD) temperaturesensor, a junction potential temperature sensor (including sensors thatuse a voltage measure across a junction as an indicator of temperature),a thermistor, an integrated-circuit temperature sensor (including aLM35-series temperature sensor), or a semiconductor temperature sensor.Example flow sensor 306′ can provide a measure of the flow rate of bloodin a tissue lumen based on temperature measurements of the temperaturesensor. In operation, the heating element is used to maintain thetemperature sensor at a specified temperature measurement value. Anyfluid flowing past the heating element and temperature sensor can causesome change or fluctuation in the temperature measurement of thetemperature sensor. The heating element is configured such that it triedto maintain the temperature sensor at the stable specified temperaturereading. A change in the fluid flow rate that causes some fluctuation inthe reading of the temperature sensor causes the heating element toincrease of decrease its heat output to bring the temperature sensor toits specified reading. A faster flow rate of the fluid (e.g., the blood)in the region of the flow sensor can cause the heating element toincrease its heat output. A slower flow rate of the fluid (e.g., theblood) in the region of the flow sensor can cause the heating element todecrease its heat output. As a result, a change in the operating pointof the heating element can be used to provide an indication of the flowrate of the fluid measurement of the temperature sensor can be used toprovide an indication of the flow rate of fluid proximate to theinflatable and/or expandable body 302.

As shown in FIG. 3B, the support 309 can be configured to separate theheating element 307 from the fluid by a value “y” as shown in FIG. 3B.The parameter “y” can be about 2 mm, about 3 mm, about 5 mm, about 8 mm,about 10 mm, about 12 mm, about 15 mm or more. For different exampleimplementations, parameters “x” and “y” can be modified to vary thedynamic range of the resulting example flow sensor. For example, “x” canbe made larger and “y” can be made smaller to increase the overall rangeof the example flow sensor. For smaller values of “y”, the heat is ableto flow to the region fluid more easily. With larger values of “x”, itcould take more power to generate enough heat to flow to the position ofthe temperature sensor “x” to bring the temperature sensor to a desiredspecified measurement setpoint. As a result, the flow sensor can beoperated over a greater overall range, including range of the operationsignal to the heating element. For example, as described hereinbelow,the level/magnitude of the signal to the heating element can be used toprovide an indication of the flow rate of the fluid. The greater rangeof the operation signal to the heating element according to thisprinciple can provide a larger range of values and a larger data assetof values for use in determining the fluid flow rate. In an exampleimplementation, the system can include a plurality of flow sensors, withtwo or more of the flow sensors configured with differing values of “x”and “y” between the heating element and temperature sensor of therespective flow sensor. As a result, the example system presents flowsensors displaying a variety of measurement ranges.

The example flow sensors according to the principles described hereincan include a temperature sensor proximate to a thermal ‘radiation’source. According to any of the example systems, methods and apparatusdescribed herein, non-limiting examples of heating elements that canprovide the thermal radiation include any form of heater that can becoupled with a catheter, including a resistive heater or athermoelectric heater.

In any example device according to the principles described herein, thetemperature sensor can include at least one of a resistance temperaturedetector (RTD) temperature sensor, a thermocouple, a junction potentialtemperature sensor (including sensors that use a voltage measure acrossa junction as an indicator of temperature), a thermistor, anintegrated-circuit temperature sensor (including a LM35-seriestemperature sensor), and a semiconductor temperature sensor. In variousexamples, a sensor of known impedance is used. Other non-limitingexamples of sensors that can be used according to any of the systems andmethods described herein include vapor deposited gold resistors andceramic thermistors. In another example, other materials such as foilscan be used.

In an example, a calibration standard can be developed for the flowsensor 306′, to correlate the operating point of the heating element toa flow rate. For example, training samples can be used to convert a flowmeasurement, each training sample being a fluid caused to flow at aspecific flow rate. For a given amount and/or rate of change ofoperating point of the heating element by the heating element, theoperating point of the flow sensor is obtained for each training sample.The flow rate of each training sample is known (given that it is pre-setfor the training samples). The amount and/or rate of heating supplied bythe heating element is also known. The calibration standard can bedeveloped to correlate the known heating supplied to the known flow rateto obtain calibration data. The example calibration standard can be usedto convert a flow sensor measurement to a flow rate for a fluid havingsimilar properties as the fluid used in the training standard.

In an example implementation, the examples device of FIGS. 3A and 3B canfurther include a flow sensor that is disposed on a portion of acatheter that is coupled to the proximal portion of the inflatableand/or expandable body.

In an example, the electronic circuit 306 can include a number ofelectrodes disposed on the inflatable and/or expandable body 302. Theelectrodes can be used to perform a procedure according to theprinciples described herein. For example, at least one of the electrodescan be a radiofrequency (RF) electrode that delivers RF energy to aportion of the tissue surface that is proximate to the RF electrode.According to the principles described herein, the delivered RF energy isused to modify the tissue, including to disrupt a renal nerve.

In another example, the device 300 can include components to perform aprocedure using other modalities. For example, the device 300 caninclude components to disrupt the renal nerve, e.g., through ablation,including through applying energy in the form of RF energy, heating, orcryo (extreme cold) to the nerves.

In another example, the electronic circuit 306 of device 300 can includeat least one pacing electrode. The pacing electrode can be implementedto deliver an electrical stimulation to a portion of a tissue (such asbut not limited to a renal artery) proximate to the pacing electrode. Asdescribed above, the pacing electrode can be used to stimulate nerve atdifferent stages of a procedure. For example, the electrical stimulationfrom the pacing electrode(s) can be applied to the portion of the tissueto stimulate nerves prior to delivery of an energy to disrupt thenerves, such as but not limited to through ablation, including throughapplying energy in the form of RF energy, heating, or cryo (extremecold) to the nerves. In another example, the electrical stimulation fromthe pacing electrode(s) can be applied to the portion of the tissue tostimulate nerves subsequent to delivery of an energy to disrupt thenerves, such as but not limited to through ablation, including throughapplying energy in the form of RF energy, heating, or cryo (extremecold) to the nerves.

In another example, the electronic circuit 306 can also includetemperature sensors, each temperature being disposed proximate to anelectrode of the electronic circuit 306.

In another example, the device 300 can include one or more othercomponents disposed on the inflatable and/or expandable body such as,but not limited to, a pacing electrode, a light-emitting device, acontact sensor, an image detector, a pressure sensor, a biologicalactivity sensors, a temperature sensor, or any combination thereof.

FIGS. 4A and 4B show a non-limiting example implementation of an exampledevice 400. The example device 400 includes an inflatable and/orexpandable body 402, a flow sensor 404 disposed on a portion of theinflatable and/or expandable body 402, and an electronic circuit 406disposed on the inflatable and/or expandable body 402. The electroniccircuit 406 includes a number of components that accommodate expandingof the inflatable and/or expandable body 402. As shown in FIGS. 4A and4B, the flow sensor 404 can be being disposed on a distal portion of theinflatable and/or expandable body 402. As a non-limiting example, aportion of the distal region of the expandable and/or inflatablestructure can be extended to form a protrusion. The flow sensor 404 canbe mounted on the protrusion. In another example, the flow sensor 404can be disposed on or proximate to a proximal portion of the inflatableand/or expandable body.

In an example implementation, the flow sensor 404 can be a formed asincluding a heating element 407 disposed proximate to a temperaturesensor 408. In various examples, the heating element 407 can beseparated from the temperature sensor 408 by about 1 mm or about 2 mm.As a non-limiting example, the heating element 407 can be atemperature-controlled heating element. As a non-limiting example, thetemperature sensor 408 can be a thermistor.

In the non-limiting example of FIGS. 4A and 4B, the electronic circuitcan include a number of electrodes 410 disposed on the inflatable and/orexpandable body 402. The electrodes can be used to perform a procedureaccording to the principles described herein. For example, at least oneof the electrodes 410 can be a radiofrequency (RF) electrode thatdelivers RF energy to a portion of the tissue surface that is proximateto the RF electrode. According to the principles described herein, thedelivered RF energy is used to modify the tissue, including to disrupt arenal nerve.

As shown in the non-limiting example of FIGS. 4A and 4B, the electroniccircuit 406 of the example device 400 can include stretchableinterconnects 412 disposed on the surface of the inflatable and/orexpandable body 402. As shown in FIG. 4B, the stretchable interconnectscan be used to electrically couple at least one of the plurality ofelectrodes 410 to an external circuit.

As shown in the non-limiting example of FIGS. 4A and 4B, the electroniccircuit 406 of the example device 400 can also include a main bus 414.As shown in FIG. 4B, the stretchable interconnects 412 electricallycouple the electrodes 410 to the man bus 414. As also shown in FIG. 4B,the main bus 414 can extend beyond the inflatable and/or expandable body402 to facilitate electrical coupling of the electrodes 410 to anexternal circuit.

In another example, the at least one of the electrodes 410 of electroniccircuit 406 of device 400 can be a pacing electrode. The pacingelectrode can be implemented to deliver an electrical stimulation to aportion of a tissue (such as but not limited to a renal artery)proximate to the pacing electrode. As described above, the pacingelectrode can be used to stimulate nerve at different stages of aprocedure. For example, the electrical stimulation from the pacingelectrode(s) can be applied to the portion of the tissue to stimulatenerves prior to delivery of an energy to disrupt the nerves, such as butnot limited to through ablation, including through applying energy inthe form of RF energy, heating, or cryo (extreme cold) to the nerves. Inanother example, the electrical stimulation from the pacing electrode(s)can be applied to the portion of the tissue to stimulate nervessubsequent to delivery of an energy to disrupt the nerves, such as butnot limited to through ablation, including through applying energy inthe form of RF energy, heating, or cryo (extreme cold) to the nerves.

In another example, the device 400 can include components to perform aprocedure using other modalities. For example, the device 400 caninclude components to disrupt the renal nerve, e.g., through ablation,including through applying energy in the form of RF energy, heating, orcryo (extreme cold) to the nerves.

In another example, the device 400 can include one or more othercomponents disposed on the inflatable and/or expandable body such as,but not limited to, a pacing electrode, a light-emitting device, acontact sensor, an image detector, a pressure sensor, a biologicalactivity sensors, a temperature sensor, or any combination thereof.

In another example, the device 400 can also include temperature sensors,each temperature being disposed proximate to an electrode 410 of theelectronic circuit 406.

FIG. 5 shows a non-limiting example implementation of an electroniccircuit 506 and flow sensor 504 that can be disposed on a catheter andextend to a shaft of an example device according to the principlesdescribed herein. The electronic circuit 506 includes a number ofelectrodes 510. In various examples, the electrodes 510 can beconformable electrodes that conform to the surface of the inflatableand/or expandable body. As shown in FIG. 5, the flow sensor 504 includesa heating element 507 disposed proximate to a temperature sensor 808. Asa non-limiting example, the heating element 507 can be atemperature-controlled heating element. As a non-limiting example, thetemperature sensor 508 can be a thermistor.

In the non-limiting example of FIG. 5, at least one of the electrodes510 can be a radiofrequency (RF) electrode that delivers RF energy to aportion of the tissue surface that is proximate to the RF electrode.According to the principles described herein, the delivered RF energy isused to modify the tissue, including to disrupt a renal nerve. At leastone of the electrodes 510 can be a pacing electrode that delivers anelectrical stimulation to a nerve, as described herein.

As shown in the non-limiting example of FIG. 5, the electronic circuit506 includes stretchable interconnects 512 disposed on the surface ofthe inflatable and/or expandable body. The stretchable interconnects 512can be used to electrically couple at least one of the plurality ofelectrodes 510 to an external circuit.

As also shown in the non-limiting example of FIG. 5, the electroniccircuit 506 also includes a main bus 514. As shown in FIG. 5, thestretchable interconnects 512 electrically couple the electrodes 510 tothe main bus 514. As also shown in FIG. 5, the main bus 514 includesconnection pads 516 that facilitate electrical coupling of theelectrodes 510 to an external circuit.

FIG. 6A shows a portion of an example device 600 that can be used toperform a procedure according to the principles described herein. Theexample device 300 includes an elongated member 602, and a flow sensor604 disposed on a distal portion of the elongated member 602. In FIG.6A, the flow sensor 604 is illustrated as being disposed on a distalportion of the elongated member. In another example, the flow sensor canbe disposed on or proximate to a proximal portion of the elongatedmember or on a proximal or distal portion of an inflatable and/orexpandable body that is coupled to the elongated member.

In this example implementation, the flow sensor can be formed asillustrated in FIG. 6A, and includes a heating element 606 and atemperature sensor 608. The heating element 606 includes a cavity 607.As shown in FIG. 6A, at least a portion of the temperature sensor 608 ishoused in a portion of the cavity 607. Similarly to as described inconnection with the flow sensor of FIGS. 3A and 3B above, the heatingelement 606 can be used to heat an area proximate to the elongatedmember 602. A temperature measurement of the temperature sensor 608 canbe used to provide an indication of the flow rate of a fluid proximateto the flow sensor 604. For example, if the fluid has a higher flow rateand wicks away heat from the area proximate to the heating element, thetemperature sensor can record a different measurement than obtained ifthe fluid flow rate is lower.

In operation, the heating element is used to maintain the temperaturesensor at a specified temperature measurement value. Any fluid flowingpast the heating element and temperature sensor can cause some change orfluctuation in the temperature measurement of the temperature sensor.The heating element is configured such that it tries to maintain thetemperature sensor at the stable specified temperature reading. A changein the fluid flow rate that causes some fluctuation in the reading ofthe temperature sensor causes the heating element to increase ofdecrease its heat output to bring the temperature sensor to itsspecified reading. A faster flow rate of the fluid (e.g., the blood) inthe region of the flow sensor can cause the heating element to increaseits heat output. A slower flow rate of the fluid (e.g., the blood) inthe region of the flow sensor can cause the heating element to decreaseits heat output. As a result, a change in the operating point of theheating element can be used to provide an indication of the flow rate ofthe fluid measurement of the temperature sensor can be used to providean indication of the flow rate of fluid proximate to the inflatableand/or expandable body 302.

As also described above in connection with the flow sensor of FIGS. 3Aand 3B, temperature sensor 608 can be a thermocouple, a resistancetemperature detector (RTD) temperature sensor, a junction potentialtemperature sensor (including sensors that use a voltage measure acrossa junction as an indicator of temperature), a thermistor, anintegrated-circuit temperature sensor (including a LM35-seriestemperature sensor), or a semiconductor temperature sensor. In variousexamples, a sensor of known impedance is used. Other non-limitingexamples of sensors that can be used according to any of the systems andmethods described herein include vapor deposited gold resistors andceramic thermistors. In another example, other materials such as foilscan be used.

The example flow sensors according to the principles described inconnection with FIG. 6A can include any type of a thermal ‘radiation’source. N on-limiting examples of heating elements that can beimplemented to provide the thermal radiation include any form of heaterthat can be coupled with an elongated member and be configured to have acavity. As non-limiting examples, the heating element can be, but is notlimited to, a resistive heater or a thermoelectric heater.

FIG. 6B shows an implementation 620 of an example flow sensor 624according to the principles of FIG. 6A. The example flow sensor 624includes a heating element 626 and a temperature sensor 628. The heatingelement 626 is formed as a spiral, helical, or other coiled resistivewire with a hollow core that provides a cavity. The resistive wire canbe formed from a high resistivity electrically material to facilitatehigher power dissipation. As shown in FIG. 6A, at least a portion of thetemperature sensor 628 is housed in a portion of the cavity. As shown inthis example, the heating element 626 and the temperature sensor 628 canbe at least partially encapsulated in a thermally conductiveencapsulant. Similarly to as described in connection with the flowsensor of FIGS. 3A and 3B above, the heating element 626 can be used toheat an area proximate to an elongated member that the flow sensor iscoupled to. A temperature measurement of the temperature sensor 628 canbe used to provide an indication of the flow rate of a fluid proximateto the flow sensor 624.

FIG. 6C shows another implementation 630 of an example flow sensoraccording to the principles of FIG. 6A. The example flow sensor includesa heating element 636 and a temperature sensor (not shown). The heatingelement 636 is formed as a patterned thin-film of a resistive material631 on a flexible and/or stretchable substrate 633. In this example, thethin-film is patterned in a boustrophedonic pattern. The heating element636 can be rolled into a more compact form factor, with at least aportion formed with a hollow core that provides a cavity. The resistivewire can be formed from a high resistivity electrically conductivematerial to facilitate higher power dissipation. Similarly to asdescribed in connection with the flow sensor of FIGS. 3A and 3B above,the heating element 636 can be used to heat an area proximate to anelongated member that the flow sensor is coupled to. A temperaturemeasurement of the temperature sensor disposed at least partially in thecavity can be used to provide an indication of the flow rate of a fluidproximate to the flow sensor 634.

FIG. 6C shows another implementation 630 of an example flow sensoraccording to the principles of FIG. 6A. The example flow sensor includesa heating element 636 and a temperature sensor (not shown). The heatingelement 636 is formed as a patterned thin-film of a resistive material631 on a flexible and/or stretchable substrate 633. In this example, thethin-film is patterned in a boustrophedonic pattern. In another example,other linear patterns can be used. The heating element 636 can be formedinto a compact form factor, with at least a portion formed with a cavity637. The thin-film can be formed from a high resistivity electricallyconductive material to facilitate higher power dissipation. Similarly toas described in connection with the flow sensor of FIGS. 3A and 3Babove, the heating element 636 can be used to heat an area proximate toan elongated member that the flow sensor is coupled to. A temperaturemeasurement of the temperature sensor disposed at least partially in thecavity can be used to provide an indication of the flow rate of a fluidproximate to the flow sensor.

FIG. 6D shows another implementation 640 of an example flow sensorcoupled to a portion of an elongated member 642 according to theprinciples of FIG. 6A. The example flow sensor includes a heatingelement 646 and a temperature sensor (not shown). The heating element646 is formed as a patterned thin-film of a resistive material 641 on aflexible and/or stretchable substrate 643. As shown in this example, thethin-film can be patterned in a stretchable pattern. The stretchablepattern allows more bending of the elongated member while compensatingfor surface strain. While the example of FIG. 6D shows a serpentinepattern, the stretchable pattern may be other stretchable pattern,including a zig-zag pattern, a wavy pattern or a rippled pattern. Theheating element 646 can be formed into a compact faint factor, with atleast a portion formed with a cavity. The thin-film can be formed from ahigh resistivity electrically conductive material to facilitate higherpower dissipation. Similarly to as described in connection with the flowsensor of FIGS. 3A and 3B above, the heating element 646 can be used toheat an area proximate to an elongated member that the flow sensor iscoupled to. A temperature measurement of the temperature sensor disposedat least partially in the cavity can be used to provide an indication ofthe flow rate of a fluid proximate to the flow sensor.

FIG. 7A shows another example device 700 that can be used to perform aprocedure according to the principles described herein. The exampledevice 700 includes an inflatable and/or expandable body 702, a pair offlow sensors 704-a and 704-b, and an electronic circuit 706 disposed onthe inflatable and/or expandable body 702. The device 700 is coupled toa distal portion of a shaft 708. The electronic circuit 706 includes anumber of components that accommodate expanding of the inflatable and/orexpandable body 702. In FIG. 7A, one of the flow sensor 704-a is shownto be disposed on a proximal portion of the inflatable body. The otherflow sensor (reference flow sensor 704-b) is shown to be disposed on aportion of shaft 708 at some distance away from the inflatable and/orexpandable body 702. In the example implementation of FIG. 7A, the flowrate can be measured based on comparison of the measurement of the pairof flow sensors 706-a and 706-b. For example, the flow rate can bemeasured based on comparison of voltage measurements of the pair of flowsensors 706-a and 706-b.

FIG. 7B shows another example device 700′ that can be used to perform aprocedure according to the principles described herein. Example device700′ includes an inflatable and/or expandable body 702, a pair of flowsensors 704-a and 704-b, an electronic circuit 706 disposed on theinflatable and/or expandable body 702, and a shaft 708, the samecomponents as example device 700, and they are not repeated. Exampledevice 700′ also includes a shaft 710 that can be disposed overreference electrode 704-b during a procedure or a flow measurement. Theexample device 710 also can be retracted to such an extent thatreference flow sensor 704-b is exposed.

In the various examples described herein, the reference sensor can bepositioned on the shaft at a location that can be covered by a sheath.FIG. 7B shows a non-limiting example of a catheter device that includesa sheath member that can be positioned to cover at least a portion ofthe reference sensor. In an example implementation, this distance can bedetermined as greater than or equal to about 10 cm away from theproximal end of the balloon. In another example implementation, thisdistance can be determined as less than about 10 cm away from theproximal end of the balloon. For example, the reference flow sensor704-b can be positioned at a distance away on the shaft of the catheterthat is at least about 5 cm, at least about 8 cm, at least about 10 cm,at least about 13 cm, at least about 15 cm or more. In an exampleimplementation, a sheath can be included and used to guide, introduceand steer the catheter. The sheath can be a member that surrounds atleast a portion of the circumference of the shaft of the catheter and/orcan be co-axial with the shaft of the catheter. During a procedure, thereference sensor can be maintained under the sheath. The sheath can beconfigured to provide a stable known environment and provide a chamberthat can include blood in the absence of flow. In this example, bloodenters the sheath but flow can be halted by the presence of a stopcockor flow switch. The blood can be maintained at body temperature but doesnot flow, thereby providing a useful comparison in proximity of thereference sensors. The measurement performed using the reference sensorin this environment of blood that is not flowing can serve as areference for comparison to the renal artery sensor.

The internal shaft near the reference sensor can include surfacefeatures in the form of bumps or tracks that provide channels for theblood. The blood forms an insulating layer on the reference sensor,allowing a reference quiescent blood temperature to be measured. Thesurface features can be designed and configured to allow blood tocirculate as freely and prevent the shaft from making contact with thesheath in that area. For example, the shaft may include one or morespacers (also referred to as protuberances) to maintain the shaft spacedapart from a portion of the surface of the sheath. The spacing apart ofthe shaft from the sheath helps to maintain a static layer of bloodstatic between the sheath and the shaft.

FIGS. 8A and 8B illustrate an operation of the flow sensors of FIG.7A-7B. FIG. 8A shows an example device 800 that includes an inflatableand/or expandable body 802, a pair of flow sensors 804-a and 804-b, anelectronic circuit 806 disposed on the inflatable and/or expandable body802, a shaft 808 and a sheath 810. Flow sensor 804-b is coupled to theshaft and covered by the sheath 810. In the example of FIG. 8B, bloodflows in the aorta and renal artery, yet blood remains static in thesheath due to a stopcock or flow switch. This allows a differentialmeasurement of flow in the renal artery versus static flow in thesheath. It also allows for better use of dynamic range since themeasurement is limited between the two sensors. As also shown in FIG.8B, the inflatable or expandable structure can be deflated or retractedat the time of flow sensor measurement.

In an example implementation, the method in connection with FIGS. 8A and8B can be used to resolve small changes in temperature in the body. Anexample system, apparatus and method according to the principlesdescribed herein can be used to measure the signal of interest inconnection with a procedure and reject information that does not relateto the signal of interest, thereby increasing resolution and reducingthe requirements for expensive signal processing.

An example system, apparatus and method according to the principlesdescribed herein can be used to measure differential flow, such asdescribed in connection with FIGS. 8A and 8B. In an exampleimplementation, two (or more) sensors are used to measure flow via achange in flow sensor operating point. As shown in FIGS. 8A and 8B, atleast one reference sensor can be placed on the shaft of a catheter usedto perform a measurement described herein. The non-limiting examplecatheter can include one or more renal artery flow sensors and/or one ormore other sensors, including one or more ablation components and/or oneor more pacing electrodes. The reference sensor can be disposed aboutthe inflatable or expandable member of the catheter, such as but notlimited to a balloon, an expandable mesh, or a deployable netting. Thereference sensor can be disposed at a sufficient separation distanceaway from the proximal end of the balloon so that the reference sensoris covered by the sheath of the catheter when it is proximate to thetissue of the body. One or more renal artery sensors can be positionedat or near the proximal end of the balloon. Each measurement taken canbe compared or displayed in reference to a measurement of the referencesensor.

Systems, methods and apparatus are described herein that can be used toincrease the dynamic range of measurements by focusing on the signal ofinterest. In an example implementation, each flow sensor, including anyreference sensor, can be excited using the same controlled currentsource. In an example implementation, each sensor can be measured usingan instrumentation amplifier. FIG. 9 shows a non-limiting examplesimplified schematic of a differential pre-amplifier that can be used tomeasure differences in voltages. The example differential pre-amplifiercircuitry can be implemented to compare measurements of flow sensorsaccording to the principles of FIGS. 8A-8B. In this non-limitingexample, the flow sensors can include thermistors. In other examples,the flow sensors can include at least one of a resistance temperaturedetector (RTD) temperature sensor, a thermocouple, a junction potentialtemperature sensor (including sensors that use a voltage measure acrossa junction as an indicator of temperature), an integrated-circuittemperature sensor (including a LM35-series temperature sensor), and asemiconductor temperature sensor. In various examples, a sensor of knownimpedance is used. Other non-limiting examples of sensors that can beused according to any of the systems and methods described hereininclude vapor deposited gold resistors and ceramic thermistors. Inanother example, other materials such as foils can be used.

In the example of FIG. 9, the difference in the voltage can be measuredbetween the flow sensors (such as but not limited to the thermistor)that are driven by an excitation current. Signal C is the differencebetween the signal from the flow sensor proximate to the inflatableand/or expandable body (renal flow sensor measurement—signal A) and thesignal from the reference flow sensor (reference flow sensormeasurement—signal B).

The instrumentation amplifiers can be used to reject common-modesignals, thereby providing a higher fidelity signal. In a non-limitingexample, an apparatus or system described herein can include thermistorsthat are well matched (used as the flow sensors in this example). Theabsolute values of the thermistor measurements can be used. A benefit ofmeasuring a reference thermistor and renal artery thermistor can beimprovement of the dynamic range by measuring the difference of thevalues between the sensors as compared to using the absolute values.Limiting the measurements between the reference and the renal arterysensor can facilitate improvement of the dynamic range of themeasurements.

An example implementation to perform a measurement is described. In anexample, the flow sensors are of known impedances, and application of anexcitation current using the flow sensors creates a voltage that ismeasured using instrumentation amplifiers. The amplifiers are used tomeasure a voltage correlating to a flow rate. Changes in blood flow canresult in a change in operating set point in at least one of the flowsensors. By comparing the value of voltage measured using the referencesensor to the value of voltage measured using a flow sensor disposedproximate to the expandable and/or inflatable body, the flow rate can bequantified. Through this comparison, the instrument voltage in theabsence of flow also can be removed. In an example, the value of voltagemeasured using the reference sensor is subtracted from the renal arterysensor voltage to provide an indication of the instrument voltage in theabsence of flow. In an example where a reference flow sensor issurrounded by a sheath, blood in the sheath is physically static. Thatis, it is not flowing and remains at body temperature. Blood in therenal artery is also at body temperature but flows at some rate (desiredto be measured).

The differential voltage comparison can be computed based on the flowsensor measurement data as follows:Differential Measurement (C)=Renal Artery Sensor Voltage (A)−ReferenceSensor Voltage (B)It also can be expressed as: C=A−BEffectively, in an example implementation, the equation can be expressedas:DifferentialMeasurement=(Voltage_(BodyTemp)+Voltage_(RenalFlow))−(Voltage_(BodyTemp)+0)where V_(SheathFlow)=0.Differential Measurement=Voltage_(RenalFlow)A gain can be added at any of the instrumentation amplifiers to increasethe amplitude of the signal.

In an example implementation, one or more flow sensors can becalibrated. An offset value between the flow sensors disposed proximateto the inflatable and/or expandable body and the reference flowsensor(s) can be eliminated by placing the catheter in a knowntemperature and flow rate, and measuring the difference between the twosets of sensors. The measurement can be performed and/or the offsetvalue can be derived at the time of manufacture of the catheter and/ortime of assembly of the flow sensors with the inflatable and/orexpandable body of the catheter. The offset value can be stored and/orindicated as a written value, or a barcode or other form ofidentification (ID). In an example, an integrated circuit or memorydevice or other means can be used to provide this value and ID to aconsole that is in communication with the catheter (including with theflow sensors disposed on or proximate to the inflatable and/orexpandable body). This offset value can be programmed into the catheter.When the catheter is coupled with the console, the console can use theoffset value to compensate for an offset in the measurements whencalculating flow.

Detecting a change in reading of a thermistor, such as in an example ofthe implementation described in connection with FIGS. 7A-7B and 8, canprovide an indication of the rate of fluid flow. Detecting flow ratechange in the renal artery can require high-resolution measurement.

For example, the differential measurement described in connection withFIGS. 7A-7B and 8 can be used in conjunction with other methods, such aspeak-to-peak measurements, synchronous-demodulation (lock-in), and threeomega (3ω) methods. In different example implementations, thedifferential measurement can be used to measure peak-to-peak output, orit can be input into a lock-in amplifier or 3ω acquisition system asshown in FIG. 10. The 3ω method can be implemented using amicro-fabricated metal pattern acting as a resistive heater. Analternating current (AC) voltage signal energizes the resistive elementat a frequency ω. The periodic heating generates oscillations in theelectrical resistance of the metal line at a frequency of 2ω. In turn,this leads to a third harmonic (3ω) in the voltage signal. The thirdharmonic is used according to an example implementation to determine themagnitude of the temperature oscillations. The temperature oscillationscan be used to provide an indication of the flow rate of a fluid. Forexample, the frequency dependence of these temperature oscillations canbe used to derive the thermal properties of the specimen (e.g., thefluid). The data indicative of the thermal properties of the specimencan be used to derive data indicative of the flow rate of the fluid.

In any of the examples described herein, the flow sensor (including the3-omega sensor) can be disposed on the example device such that the flowsensor is disposed within a mid-point of a tissue lumen when the exampledevice is disposed within the lumen. The mid-point of the lumen intissue (including the renal artery lumen) can be the location of maximumflow velocity). The central positioning of the flow sensor canfacilitate more accurate measured of fluid flow rate by sampling thearea of maximum flow.

FIG. 11 illustrates an example device that is comprised of a flow sensor1154 disposed on a distal portion of a rod catheter or guidewire 1152, areference temperature sensor 1156 disposed on a proximal portion of therod catheter or guidewire 1152, and a sheath 1158. Reference temperaturesensor 1156 is coupled to the shaft and may be covered by the sheath1158 or may remain uncovered. In the example of FIG. 11, the system canbe operated such that a specified difference can be maintained betweenthe value of the temperature measurement of the reference temperaturesensor 1156 and the value of the temperature measurement of thetemperature sensor of the flow sensor 1154. As described in greaterdetail below, the temperature difference can be maintained at a value oftemperature difference of about 1.5° C., about 2.0° C., about 2.5° C.,about 3.0° C., about 3.5° C., about 4.0° C., or about 4.5° C. While theexamples of FIGS. 7A through 8B are described as having a reference flowsensor (704-b or 810), each system can be operated as described inconnection with FIG. 11, but with the reference flow sensor replacedwith a reference temperature sensor.

In an example implementation, a device according to any of theprinciples herein and in any of the figures, including FIGS. 3A through8B or FIG. 11, can be implemented to performing a medical treatmentprocedure on a tissue as follows. The example device includes anelongated member, a flow sensor disposed proximate to a distal portionof the elongated member, and a reference temperature sensor disposedproximate to a proximal portion of the elongated member. The flow sensorand the reference temperature sensor are in communication with a controlmodule. In this example, the control module is used to maintain atemperature difference between the measurement of the referencetemperature sensor and the measurement of the temperature sensor of theflow sensor. For example, the control module can be used to monitor thetemperature measurement(s) of the reference temperature sensor and/orthe temperature measurement(s) of the temperature sensor of the flowsensor at various stages of the procedure being performed. Based on themonitoring, the control module can generate signals to the heatingelement to cause it to emit heat or discontinue emitting heat, such thatthat the temperature difference is maintained. The signal(s) applied tothe heating element can be stored to a memory, transmitted using acommunication interface or a communication protocol, and/or read out toa user interface (such as a display).

The temperature difference can be maintained as a constant temperaturedifference or a time-varying temperature difference. For example, aconstant temperature difference can be maintained at about 1.5° C.,about 2.0° C., about 2.5° C., about 3.0° C., about 3.5° C., about 4.0°C., or about 4.5° C.

In an example, the control module includes aproportional-integral-derivative (PID) controller. FIG. 12 shows anexample control system for implementing a PID controller control loop.As shown in FIG. 11, the PID controller receives as input a voltagesignal 1202 from the temperature sensor of the flow sensor and a voltagesignal 1204 from the reference temperature sensor. At 1206, the PIDcontroller applies an algorithm and associated method to determine thethree-term controls: the proportional (P), the integral (I), and thederivative (D) values. Based on these computations, the PID controllerdetermines the error or degree of deviation of the measured signals fromthe temperature sensors from the expected values that would maintain thedesired temperature difference between them. The PID controller appliesa heating element control algorithm (and associated method) to thecombination of P, I, and D values to determine a signal to send to avoltage controlled current source 1210 to the heating element 1212. Thesignal sent to the voltage controlled current source 1210 causesadjustments to the power to the heating element, to cause it to emitheat, or discontinue emitting heat. That is, applying the PID controllerinvolves comparing the value of the temperature measurement of thereference temperature sensor to the temperature measurement of thetemperature sensor of the flow sensor, determining a signal, e.g., a PIDcorrection signal, based on the comparison, and using the control moduleto determine the signal to the heating element based on the PIDcorrection signal. As a result of the feedback from the temperaturesensors to the PID controller, the system can minimize the deviation ofthe measured signals from the temperature sensors from the expectedvalues that would maintain the desired temperature difference betweenthem. In an example, the system can include hardware to generate asinusoidal current with a fixed frequency but varying amplitude for theheating element.

In an example implementation, the control module can be configured tomaintain a constant temperature difference, such as but not limited toabout 2° C., between the reference temperature sensor and thetemperature measured at the temperature sensor of the flow sensor. Forexample, the heating element can be powered to heats the temperaturesensor of the flow sensor (e.g., a thermistor) to about 39° C. The useof the control module as described herein maintains this temperaturedifference, such that the reference temperature sensor is maintained ata constant temperature difference of about 2° C., i.e., at about 37° C.The signal applied to the heating element can be stored to a memory,transmitted using a communication interface, and/or read out to a userinterface (such as a display).

In another example implementation, the control module can be configuredto maintain a constant temperature difference while the example deviceis being used during a procedure, e.g., nerve stimulation, ablation orother denervation procedure. If fluid flow rate increases during theprocedure, the increased fluid flow rate removes heat from the region ofthe flow sensor (the coupled heating element and temperature sensor).The control module determines from the control loop that the temperaturedifference is deviating from the desired value (e.g., a temperaturedifference falling below about 2° C.). The control module generates asignal to cause the heating element to emit heat, to return thetemperature difference to the desired value (e.g., a value of about 2°C.). The signal applied to the heating element can be stored to amemory, transmitted using a communication interface, and/or read out toa user interface (such as a display). In this case, the signal couldshow an increase, since as it sending controls to cause the heatingelement to emit heat.

In an example implementation where a stage of the procedure causes thefluid flow rate to decrease, the decreased fluid flow rate removes lessheat from the region of the flow sensor (the coupled heating element andtemperature sensor). The control module determines from the control loopthat the temperature difference is deviating from the desired value(e.g., a temperature difference may be increasing to above about 2° C.).The control module generates a signal to cause the heating element tocease emitting heat, to return the temperature difference to the desiredvalue (e.g., a value of about 2° C.). The signal applied to the heatingelement can be stored to a memory, transmitted using a communicationinterface, and/or read out to a user interface (such as a display). Inthis case, the signal could show a decrease, since as it sendingcontrols to cause the heating element to cease emitting heat.

More precise temperature measurement, i.e., measurements that avoid theinfluence of changes in body temperature, may be obtained through use ofdifferential temperature measurement according to the principles herein.The differential temperature measurement can be performed using two ormore temperature sensors, including a reference temperature sensor thatis not coupled to a heating element; and a sense temperature sensor thatis coupled to and heated by a heating element (forming a flow sensor).The temperature sensor coupled with the heating element may be disposedon a distal portion or a proximal portion of an elongated member such asbut not limited to a rod catheter or a guidewire, or a distal portion ora proximal portion of an elongated member that includes an inflatableand/or expandable body. In an example, the reference temperature sensorcan be disposed at least about 0.5 cm, at least about 1 cm, at leastabout 1.5 cm, or at least about 2 cm or more distance spaced apart fromthe flow sensor.

In an example, a device according to any of the principles herein and inany of the figures, including FIGS. 3A through 8B or FIG. 11, caninclude two or more flow sensors, including a plurality of flow sensors.The two or more flow sensors can be coupled via the control module to asingle reference temperature sensor, or each flow sensor may be coupledto a respective reference temperature sensor.

In an example implementation, the signal to the heating element can be atime-varying voltage signal. For example, the excitation of the heatingelement and the temperature sensor of the flow sensor can be using an ACfrequency greater than the inverse of tissue response time. Asnon-limiting examples, signals at AC frequencies ranging from about 1kHz to about 100 kHz can be used to drive the flow sensor to reduce therisk of accidentally causing fibrillation. Operating at frequencies inthis range also allows for higher current leakage.

In an example implementation, the signal to the heating element can be avoltage signal, a current signal, a digital signal, or any other signalthat transmits instructions to cause the heater to heat at a desiredtemperature to maintain the desired temperature difference. The signalcan be read out and/or plotted, stored to a memory, or otherwisecommunicated or transmitted.

In an example implementation, the control signal can be mapped to a flowrate through the analysis of multiple data runs and measurements, togenerate a standard or other calibration chart that relates a value of acontrol signal to the physiological flow rate.

In an example, novel signal processing algorithms and associatedmethods, and control modules (including PID controller software) areprovided for sensing and/or quantifying fluid flow rates.

FIG. 13 shows an example demodulation that can be implemented to extractthe signal to the heating element from the noise in the signal. As anon-limiting example, processor-executable instructions that create aphase-locked loop (PLL) can be applied with a synchronous demodulationmethod to reject noise and derive the signal. At least one phase-lockedloop can be used to lock-in the sensing signal to the control signal,and the sensing signal to the heater signal for thesynchronous-demodulation. Since the same frequency is used to demodulatethe data, the desired signal is extracted as a DC signal (representingthe amplitude modulation). The synchronous demodulation provides anarrow band filter to reject noise injected by the environment of thedevice, which can interfere with the desired signal.

The capability of the temperature difference measurements and thecontrol module facilitate measurement of pulsatile flow over a broaddynamic range. As a result, systems and methods herein provide a way todetermine a clinical endpoint during a procedure, such as but notlimited to a carotid sinus denervation, a carotid body disruption, avagus nerve stimulation, a pulmonary artery denervation, a celiacganglion disruption, a bladder trigone ablation, or a renal denervationprocedure.

In an example, any system or device according to the principlesdescribed herein may be entirely or at least partially encapsulated byan encapsulating material, such as a polymer material (including any ofthe polymer materials described herein). An encapsulating material canbe any material that can be used to laminate, planarize, or encase atleast one component of a system or device described herein, includingany electronic or other type of component. For example, a method offabricating any system or device according to the principles describedherein can further include encapsulating the system or device. In anexample, an encapsulating material can be disposed over, or otherwiseapplied to, an device that includes an inflatable and/or expandable bodyand the electronic circuit or a plurality of electrodes. In an example,a polyurethane can be used as the encapsulating material. In anotherexample, the encapsulating material can be the same material as thematerial for the inflatable and/or expandable body. Encapsulating anyportion of the systems or device described herein can be useful toenhance the mechanical stability and robustness of the system or device,or to maintain electronic performance of the electronic components ofthe system or device against a stress or strain applied to the system ordevice during use.

In any of the example devices according to the principles describedherein, the encapsulating material can be formed from any materialhaving elastic properties. For example, the encapsulating can be formedfrom a polymer or polymeric material. Non-limiting examples ofapplicable polymers or polymeric materials include, but are not limitedto, a polyimide, a polyethylene terephthalate (PET), a silicone, or apolyeurethane. Other non-limiting examples of applicable polymers orpolymeric materials include plastics, elastomers, thermoplasticelastomers, elastoplastics, thermostats, thermoplastics, acrylates,acetal polymers, biodegradable polymers, cellulosic polymers,fluoropolymers, nylons, polyacrylonitrile polymers, polyamide-imidepolymers, polyarylates, polybenzimidazole, polybutylene, polycarbonate,polyesters, polyetherimide, polyethylene, polyethylene copolymers andmodified polyethylenes, polyketones, poly(methyl methacrylate,polymethylpentene, polyphenylene oxides and polyphenylene sulfides,polyphthalamide, polypropylene, polyurethanes, styrenic resins, sulphonebased resins, vinyl-based resins, or any combinations of thesematerials. In an example, a polymer or polymeric material herein can bea DYMAX® polymer (Dymax Corporation, Torrington, Conn.). or other UVcurable polymer, or a silicone such as but not limited to ECOFLEX®(BASF, Florham Park, N.J.).

For applications in biomedical devices, the encapsulant should bebiocompatible. The stretchable interconnects can be embedded in apolyimide that also acts as a mechanical reinforcement.

In an example, any of the systems or device according to the principlesherein can be disposed on the inflatable and/or expandable body suchthat a functional layer of the system or device lies at a neutralmechanical plane (NMP) or neutral mechanical surface (NMS) of the systemor device. The NMP or NMS lies at the position through the thickness ofthe device layers for the system or device where any applied strains areminimized or substantially zero. In an example, the functional layer ofa system or device according to the principles described herein includesthe plurality of sensing elements, the coupling bus, and/or thestretchable electronic system that includes the flexible annularinterconnect and the plurality of electrodes.

The location of the NMP or NMS can be changed relative to the layerstructure of the system or device through introduction of materials thataid in strain isolation in various layers of the system or device. Invarious examples, polymer materials described herein can be introducedto serve as strain isolation materials. For example, the encapsulatingmaterial described hereinabove can be used to position the NMP or NMS,e.g., by varying the encapsulating material type and/or layer thickness.For example, the thickness of encapsulating material disposed over thefunctional layers described herein may be modified (i.e., decreased orincreased) to depress the functional layer relative to the overallsystem or device thickness, which can vary the position of the NMP orNMS relative to the functional layer. In another example, the type ofencapsulating, including any differences in the elastic (Young's)modulus of the encapsulating material.

In another example, at least a partial intermediate layer of a materialcapable of providing strain isolation can be disposed between thefunctional layer and the inflatable and/or expandable body to positionthe NMP or NMS relative to the functional layer. In an example, theintermediate layer can be formed from any of the polymer materialsdescribed herein, aerogel materials or any other material withapplicable elastic mechanical properties.

Based on the principles described herein, the NMP or NMS can bepositioned proximate to, coincident with or adjacent to a layer of thesystem or device that includes the strain-sensitive component, such asbut not limited to the functional layer. The layer can be considered“strain-sensitive” if it is prone to fractures or its performance can beotherwise impaired in response to a level of applied strain. In anexample where the NMP or NMS is proximate to a strain-sensitivecomponent rather than coincident with it, the position of the NMP or NMSmay still provide a mechanical benefit to the strain-sensitivecomponent, such as substantially lowering the strain that wouldotherwise be exerted on the strain-sensitive component in the absence ofstrain isolation layers. In various examples, the NMS or NMP layer isconsidered proximate to the strain-sensitive component that provides atleast 10%, 20%, 50% or 75% reduction in strain in the strain-sensitivecomponent for a given applied strain, e.g., where the inflatable body isinflated.

In various examples, the encapsulating material and/or the intermediatelayer material may be disposed at positions coincident with thestrain-sensitive component, including in the functional layer. Forexample, portions of the encapsulating material and/or the intermediatelayer material may be interspersed with the strain-sensitive component,including at positions within the functional layer.

In any of the example devices according to the principles describedherein, portions of the stretchable interconnects, the electrodes andportions of the main bus can be formed from a conductive material. Inany of the examples described herein, the conductive material can be butis not limited to a metal, a metal alloy, a conductive polymer, or otherconductive material. In an example, the metal or metal alloy of thecoating may include but is not limited to aluminum, stainless steel, ora transition metal (including copper, silver, gold, platinum, zinc,nickel, titanium, chromium, or palladium, or any combination thereof)and any applicable metal alloy, including alloys with carbon. In othernon-limiting example, suitable conductive materials may include asemiconductor-based conductive material, including a silicon-basedconductive material, indium tin oxide or other transparent conductiveoxide, or Group III-IV conductor (including GaAs). Thesemiconductor-based conductive material can be doped.

In any of the example structures described herein, the stretchableinterconnects can have a thickness of about 0.1 μm, about 0.3 μm, about0.5 μm, about 0.8 μm, about 1 μm, about 1.5 μm, about 2 μm or greater.The buffer structure and/or flexible base can have a thickness of about5 μm, about 7.5 μm, about 9 μm, about 12 μm or greater. In any exampleherein, the encapsulant can have a thickness of about 100 μm, about 125μm, about 150 μm, about 175 μm, about 200 μm, about 225 μm, about 250μm, about 300 μm or greater.

FIGS. 14A and 14B show cross-sectional layering structure of variouscomponents of the example devices described herein, which can bemicrofabricated. FIG. 14A shows the layering structure of an electrode,which includes a polymer layer 1402, a layer of conductive material1404, and an annular structure of a polymer 1406 about a perimeter ofthe electrode. FIG. 14B shows the layering structure of a stretchableinterconnect, which includes a polymer layer 1402, a layer of conductivematerial 1404, and a layer of a polymer 1406. FIG. 14C shows thelayering structure of a flow sensor disposed on the inflatable and/orexpandable body, which includes a polymer layer 1402, a layer ofconductive material 1404, a layer of a polymer 1406, a flow sensor 1408,and an encapsulating layer 1410. In an example, the components can befabricated on a carrier substrate, released from the carrier substrate,and disposed on the inflatable and/or expandable body.

A non-limiting example fabrication process for the example device ofFIGS. 14A and 14B is as follows. The electrode can be fabricated using amicrofabrication and transfer printing process to be between about 1micron and about 5 microns thick. The sensors can be 3-omega sensors(described below) and the surface mount components (including the flowsensors) can be fabricated using use pure gold or Cu—Au—Ni fabricationtechniques. The fabricated electronic structure are integrated on thesurface of an inflatable and/or expandable body (such as but not limitedto a balloon of a catheter). In the example device structures of FIGS.14A and 14B, the polyimide can be about 25 microns in thickness. Apolyurethane, formed of a resin and a solvent, can be used as anencapsulant to planarize the array of electrodes and other components onthe surface of the inflatable and/or expandable body. The encapsulanthelps to provide durability during sheath insertion of the exampledevice into a tissue lumen.

In an example, the micro-fabricated flow sensors, electrode arrays(including ablation RF electrodes), electronics and other components ofthe example device are ultrathin, and have mechanical propertiessubstantially similar or matched with the mechanical properties of theinflatable or expandable surface.

Systems and methods are described for performing a procedure on atissue, including a renal artery, using any example device describedherein. The example method includes disposing an example device inproximity to the tissue, applying the treatment to be applied to thetissue, and recording the flow measurement of the flow sensor asdescribed herein to provide an indication of the flow rate of a fluid inproximity to the example device.

In an example, the treatment can include applying an ablation orapplying energy in the form of RF energy, heating, or cryo (extremecold) to the tissue. In an example, the treatment is performed todisrupt nerves in proximity to the tissue.

In an example, the method can be performed with an example device thatincludes a flow sensor element configured as a heating element inproximity to a temperature sensor. In this example, the operating pointof the heating element can be monitored to provide an indication of flowrate. In an example, the recording of the flow measurement of the flowsensor can be performed subsequent to applying the RF energy to thesurface of the tissue proximate to the RF electrode. In another example,the recording of the flow measurement of the flow sensor can beperformed prior to the applying of the RF energy to the surface of thetissue proximate to the RF electrode.

In an example, the temperature measurement may be performed before andafter application of the RF energy, to obtain an indication of the flowrate of the fluid (such a blood) prior to and subsequent to thetreatment procedure being performed.

In an example, systems, methods and devices for monitoring an efficacyof, determining a clinical endpoint for, a procedure. According to theprinciples described herein, the procedure can be any procedure todisrupt the renal nerves, such as but not limited to an ablation,including through applying energy in the form of RF energy, heating, orcryo (extreme cold) to the nerves. The procedure is not performedcompleted blindly with no feedback on the success of the procedure, withpotential risk of damage to tissue. The example systems, methods anddevices described herein provide an assessment of a renal denervationprocedure based on renal hemodynamics (including based on the measuresof fluid flow rate).

In any example described herein, an assessment module is providedaccording to the systems and methods described herein, where theassessment module includes a processor and a memory storing processorexecutable instructions. Execution of the processor executableinstructions causes the assessment module to perform the activitiesassociated with any method described herein, including using the dataindicative of flow rate to provide an indication of the efficacy of aclinical procedure.

In an example, the example method can include using an indication of anincrease in the flow rate of the fluid subsequent to the performance ofthe treatment as an indicator of the efficacy of the treatment procedureto disrupt the nerves (including the efficacy of applying the RF energyto the tissue). For example, a pre-set value of fluid flow rate orclinically desired percentage increase in flow rate can be used as anindicator of the efficacy of the procedure, including being used as anindication of an end-point of performance of the procedure. As anon-limiting example, a baseline flow rate can be measured using theflow sensors described herein prior to performing the procedure todisrupt the nerves. A desired pre-set value of fluid flow rate orclinically desired percentage increase in flow rate can be determinedbased on the baseline flow rate. For example, the pre-set value of fluidflow rate or clinically desired percentage increase in flow rate can beset as the amount needed to return the flow rate to an average, mean ormedian range of values for renal blood flow rate. In a feedbackassessment, the procedure can be performed, the flow rate subsequentlyre-measured/re-determined based on flow sensor measurement dataaccording to the principles described herein, and the re-measured flowrate compared to the pre-set value of fluid flow rate or clinicallydesired percentage increase in flow rate. If the desired pre-set valueof fluid flow rate or clinically desired percentage increase in flowrate is not attained, the procedure can be repeated and the flow ratere-measured. If the desired pre-set value of fluid flow rate orclinically desired percentage increase in flow rate is attained, itsignals the endpoint, and the procedure can be discontinued. In anexample, the example method can include using an indication of little orno increase in the flow rate of the fluid subsequent to the performanceof the treatment as an indicator of a lack of the efficacy of thetreatment (including the efficacy of applying the RF energy to thetissue), or as an indication that the treatment procedure should berepeated, discontinued or modified. If the desired pre-set value offluid flow rate or clinically desired percentage increase in flow rateis not attained, the procedure can be modified to achieve the desiredoutcome. In an example, the feedback of performing the procedure,re-measuring the flow rate and comparing to the pre-set value of fluidflow rate or clinically desired percentage increase in flow rate can berepeated until the endpoint is signaled.

While the assessment is described relative to a procedure on a renalartery, the assessment of the efficacy of a procedure can be performedin other systems. For example, an assessment described herein fordetermining the efficacy of a procedure using flow measurements can beapplied to procedures being performed in other tissue lumen, such aspulmonary veins, coronary arteries, peripheral blood vessels, cardiaclumen, and any other lumen in which flow can be assessed.

In an example, the method can include activating at least one pacingelectrode of the example device to deliver an electrical stimulation toa portion of the tissue proximate to the pacing electrode. For example,the method can include delivering the electrical stimulation to theportion of the tissue proximate to the pacing electrode prior torecording a flow measurement (including recording a flow measurement ofa flow sensor).

A non-limiting example process sequence, for performance of a procedureon renal artery tissue using an example device that is configured as aballoon catheter, is as follows:

-   -   Perform initial measurement (e.g., obtain a baseline flow)    -   Inflate catheter balloon to block blood flow    -   Measure renal flow using any of the example devices or methods        described herein    -   Pace the renal artery (e.g., apply electrical signals to tissue        using electrodes of the system)    -   Deflate catheter balloon    -   Measure “pre-ablation” flow using any of the example devices or        methods described herein    -   Inflate catheter balloon    -   Perform ablation of the renal artery (e.g., apply energy to        tissue to induce lesions and necrosis, including RF energy,        heating, and cryoablation)    -   Deflate catheter balloon    -   Measure “post-ablation” flow using any of the example devices or        methods described herein

A non-limiting example process sequence, for renal denervation on renalartery tissue using an example device that is configured as a ballooncatheter, is as follows:

-   -   Pace the renal artery (e.g., apply electrical signals to tissue        using electrodes of the system)    -   Measure “pre-ablation” flow rate using any of the example        devices or methods described herein    -   Perform ablation of the renal artery (e.g., apply energy to        tissue to induce lesions and necrosis, including RF energy,        heating, and cryoablation)    -   Pace the renal artery (e.g., apply electrical signals to tissue        using electrodes of the system)    -   Measure “post-ablation” flow rate using any of the example        devices or methods described herein

The flowchart of FIG. 15 shows another non-limiting example method forperforming an assessment during performance of a procedure, including anablation procedure. In this example, a two-fold or three-fold increasein blood flow rate in the renal artery is the pre-set condition used asan indicator of an endpoint of applying the procedure in a feedbackassessment. In block 1502, a baseline flow rate is measured. In block1504, a procedure is performed on the tissue, such as but not limitedto, a procedure performed using an example device described herein. Inblock 1506, the flow rate subsequently re-measured/re-determined basedon flow sensor measurement data according to the principles describedherein. In block 1508, in a feedback assessment, the re-measured flowrate is compared to the pre-set value of fluid flow rate or clinicallydesired percentage increase in flow rate. If the desired pre-set valueof fluid flow rate or clinically desired percentage increase in flowrate is attained (block 1510), it signals the endpoint (1512), and theprocedure can be discontinued. If the desired pre-set value of fluidflow rate or clinically desired percentage increase in flow rate is notattained (block 1514), the procedure can be repeated (block 1516) andthe flow rate re-measured and compared to the pre-set value of fluidflow rate or clinically desired percentage increase in flow rate (1518).If the desired pre-set value of fluid flow rate or clinically desiredpercentage increase in flow rate is attained (block 1520), it signalsthe endpoint (1512), and the procedure can be discontinued. If thedesired pre-set value of fluid flow rate or clinically desiredpercentage increase in flow rate is not attained (block 1522), theprocedure can be modified to achieve the desired outcome. For example,as shown in block 1524, the position of the instrument can be changed tosome other region of the tissue and the treatment procedure repeated. Inan example, the feedback of performing the procedure, re-measuring theflow rate and comparing to the pre-set value of fluid flow rate orclinically desired percentage increase in flow rate can be repeateduntil the endpoint is signaled.

In an example, an assessment module is provided according to the systemsand methods described herein, where the assessment module includes aprocessor and a memory storing processor executable instructions.Execution of the processor executable instructions causes the assessmentmodule to perform any of the example methods described herein, includingin connection with FIG. 15.

The example systems, methods and apparatus herein can be used to improvethe monitoring of stages of performance of a procedure as well as thecompletion of the procedure. Measurement of pulsatile fluid flow priorto performance of a procedure being performed can be used to providequantitative values for parameters indicative of a baseline fluid flow.Measurement of pulsatile fluid flow during pre-cycle and post-cyclesduring performance of a procedure can be used to provide feedback, e.g.,to a clinician or other practitioner, on the efficacy of the procedure.Based on an analysis of the flow rate measurements, the end-point of aprocedure can be determined. For example, the method can be implementedfor sensing and treatment in a tissue lumen. For example, in a renaldenervation procedure, the elongated body can be inserted into a sheathand guided through the femoral vein until it reaches the renal artery.Sensors can be used to map or image renal nerves, deliver ablationenergy, or monitor tissue properties, in conjunction with measurement offluid flow rates, before, during, and after an ablation procedure orother procedure.

In an example, the efficacy of the performance of stages of a procedurecan be monitored through an analysis of the time-dependence of the fluidflow rates. For example, a change in a time constant associated with theflow rate can be used as a measure of the efficacy a given stage in theperformance of procedure. An example method based on analysis of thetime-constant is as follows. Any example device herein, comprising anyof the flow sensors, can be disposed proximate to the tissue. In thisexample, the device includes at least one component configured to applythe pacing, ablative, denervation, or any other treatment procedurebeing performed. The at least one component to perform the treatmentprocedure on the portion of the tissue is activated, and the at leastone flow sensor is used to perform at least one flow measurement. Eachof the at least one flow measurement could be used to provide dataindicative of a change in the flow subsequent to the treatment procedureof a fluid proximate to the apparatus. An analysis of the dataindicative of the flow of the fluid can be used to determine at leastone time-constant associated with the data. For example, as shows inFIG. 16, a time constant (τ₀) may be associated with a flow rateresponse prior to performance of a procedure, while obtaining flowhaving a different time constant (τ_(d)) can be deemed an indicator ofthe end-point of the procedure. The at least one time-constantassociated with the data can be compared to a time-constant indicativeof the flow of the fluid prior to performance of the treatmentprocedure, Any observed differences can be used to provide an indicationof the efficacy of the treatment procedure.

In an example, multiple stages of the procedure can be repeated untilthe difference is low, or falls in a previously-specified range ofvalues. Based on this analysis, an indication of an endpoint of atreatment procedure can be provided or displayed.

In an example, the time constant can be analyzed to provide a measure ofthe rate of change in the flow from a highest value following thetreatment procedure to a steady-state value at a later time. An examplemethod can include determining a first order rate of change with time ofthe at least one time constant and/or a second order rate of change withtime of the at least one time constant. Another example method caninclude comparing the first order rate of change with time of the atleast one time constant to a standard for the first order rate ofchange, where the comparison provides a second indication of theefficacy of the medical treatment procedure. Comparing the second orderrate of change with time of the at least one time constant to a standardfor the second order rate of change can be used to provide an indicationof the efficacy of the medical treatment procedure.

In an example, the values of time constant and/or flow rate datagathered from a plurality of subject having a known condition can beused to provide an indication of a degree of success of a procedure or apotential for recovery from the procedure of an unclassified subject.The analysis of the values of time constant and/or flow rate datagathered from a plurality of previously classified subject can be usedto provide parameter indicative of a likelihood of success of theprocedure, the projected recovery time, and/or a risk of relapse ofsubject. The classified subjects have previously undergone any one ormore procedures. The values of time constant and/or flow rate data mayhave been gathered prior to, during, and/or after completion of the oneor more procedures. The values of time constant can include the firstorder measure of the time constant, the first-order rate of change(first derivative) of the time constant, and/or the second-order rate ofchange (second derivative) of the time constant. Any number of theplurality of known subjects may have been classified as to the degree ofsuccess of the procedure performed, the observed recovery time, and/orthe incidence of relapse of subject(s). The values of time constantand/or flow rate data gathered from the plurality of subjects, and theclassified parameters of their known conditions, can be used to train aclassifier. The classifier can be generated as a look-up table, acalibration standard, or a machine-learning tool. For example, thevalues of time constant and/or flow rate data gathered from theplurality of subjects, and the classified parameters of knownconditions, can be used to train a machine-learning tool to provide thesubject classifier (or patient classifier).

The classifier can be used to take as input data from an unclassifiedsubject, and generate as output an indication of a classification of acondition of that subject. For example, the classifier could be used toclassify the subject as to a likelihood of success of the procedure, theprojected recovery time, and/or a risk of relapse. In operation, dataindicative of a flow rate of an unclassified subject can be gatheredprior to, during, and/or after completion of a procedure, and providedas input to the classifier. The classifier can output the indication ofthe classification of the subject. In an example, the result from theclassification of the unclassified subject may result in modification ofthe procedure while it is being performed (e.g., if the classifierindicates a potential for a relapse), used as an indication of theendpoint of the procedure, and/or result in a determination of anoptimal recovery or rehabilitation regimen. In an example, theclassification of the subject using the classifier can be used todetermine at least one drug, biologic, or other substance to beadministered to the subject.

The example machine-learning tools can be supervised learning tools(including support vector machines), unsupervised learning tools(including clustering analysis), or semi-supervised learning tools. Asnon-limiting examples, the learning tool can be an artificial neuralnetwork (ANN), a Bayesian network, a decision tree, or any otherapplicable tool.

In an example, a system, apparatus and method is provided for monitoringa hemodynamic effect during a medical treatment procedure performed on avascular tissue. Parameters indicative of the hemodynamics of the fluidflow indicate the motion or equilibrium state of the fluid. The methodcan include disposing in proximity to the tissue an example deviceaccording to the principles described herein (such as but not limited toan example device as described in connection with any of FIG. 3A-8B, 11,or 23-27). At least one component of the example device to perform amedical treatment procedure on the portion of the tissue is activated. Asubstance that causes a change in dimension of the vascular tissue isadministered. At least one flow sensor of the example device is used toperform at least one flow measurement. The at least one flow measurementprovides data indicative of a change in the flow of a fluid proximate tothe example device subsequent to the medical treatment procedure. Thedata indicative of the flow of the fluid is analyzed to determine atleast one parameter indicative of the change in the hemodynamics of thefluid. A reduction in the change in the hemodynamics of the fluid can beused as an indicator of the efficacy of the medical treatment procedure.

The at least one component can be, but is not limited to, an ablativecomponent. The medical treatment procedure can be, but is not limitedto, a denervation procedure.

In an example, several stages of the method can be repeated until therate of reduction of the change in the hemodynamics of the fluid fallsbelow a specified value. In an example, an indication of an endpoint ofthe medical treatment procedure can be generated when the rate ofreduction of the change in the hemodynamics of the fluid falls below thespecified value. The example method can include displaying theindication of the endpoint of the medical treatment procedure on adisplay, as described in greater detail below.

The substance can include an endogenous substance and/or an exogenoussubstance. For example, the substance can include a calcium channelblocker, a cAMP-mediated stimulant, or a nitrovasodilator. In anotherexample, the substance can include a dopamine, adenosine, prostacyclin,saline, or nitric oxide. The substance can include a vasodilationsubstance or a vasoconstriction substance.

FIG. 17 shows a block diagram of an example system including anassessment module, according to the systems and methods describedherein. A non-limiting example of the system 1700 according to theprinciples described herein is illustrated in FIG. 17. The system 1700includes at least one communication interface 1711, at least one memory1712, and at least one processing unit 1713. The at least one processingunit 1713 is communicatively coupled to the at least one communicationinterface 1711 and the at least one memory 1712. The at least one memory1712 is configured to store processor-executable instructions 1714 andan assessment module 1715. As described in greater detail herein, theassessment module 1715 can be applied to determine, based on the flowsensor measurement data 1716, the indication of the flow rate of fluidin the tissue lumen, including to perform a differential comparison offlow sensor measurements or using the measures of flow rate to providean indication of the efficacy of a procedure being performed on thetissue (such as but not limited to a procedure to disrupt nerves). In anon-limiting example, the at least one processing unit 1713 executes theprocessor-executable instructions 1714 stored in the memory 1712 atleast to provide the feedback described herein during performance of aprocedure. The at least one processing unit 1713 also executesprocessor-executable instructions 1714 to control the memory 1712 tostore, or to control the communication interface 1711 to transmit 1717to, e.g., a user interface or to a controller for any of the exampledevices described herein, at least one of an indication of the flowrate, an indication of an endpoint for the procedure, an indication ofan efficacy of the procedure, and a suggested modification of theprocedure.

In any example implementation according to the principles describedherein, readings of 3-omega sensors can be used as the flow sensor onany of the devices described herein to provide an indication of the rateof flow of the fluid. The 3-omega sensors have similar fabricationprocessing steps as the pacing electrodes or the ablation electrodes.FIG. 18A shows a non-limiting example of a 3-omega sensor. The 3-omegasensors have intricate filamentary patterns, which can survive extrememechanical bending and twisting and yet maintain performance. The3-omega sensors measure blood flow by assessing minute changes in localtemperature. Example results collected in a perfusion chamber withpreset flow rates are shown in FIG. 18B. The 3-omega sensors can bedisposed proximate to the inflatable and/or expandable body (includingat the distal portion of the catheter). The 3-omega sensor can bedisposed on the example device such that the 3-omega sensor is disposedwithin a mid-point of a tissue lumen (location of maximum flow velocity)and three other locations near the wall of the tissue lumen. Datacollected across multiple 3-omega sensors in this configuration canfacilitate flow rate measurements at multiple positions inside thetissue lumen. The sensitivity of the 3-omega sensors (such as theexample of FIG. 18A) is in the range compatible with blood flow ratesthat exist in vivo (˜5-50 cm/s flow rates).

In any example implementation according to the principles describedherein, the flow sensing can be performed using other techniques. Forexample, an ultrasound measurement can be performed to provide anindication of the rate of flow of fluid pre-renal denervation procedureand/or post-renal denervation procedure to provide the feedback fordetermining the end-point or a procedure or to determine whether theprocedure should be modified. As another example, an optical measurementcan be used to provide the indication of the rate of flow of fluidpre-renal denervation procedure and/or post-renal denervation procedureto provide the feedback for determining the end-point or a procedure orto determine whether the procedure should be modified. Other applicableflow sensing technology is a time-of-flight measurement, where the flowbehavior of a tracker fluid introduced into the renal artery is measuredto used to provide the indication of the rate of flow of fluid pre-renaldenervation procedure and/or post-renal denervation procedure.

Fluid flow monitoring before, during and after delivery of nerve pacingand delivery of a treatment according to the principles described herein(including ablation energy) are powerful capability sets, that whenoffered in a single spiral catheter, can enhance the efficacy of atreatment procedure (including a renal denervation procedure).Variations in blood flow change the local steady-state temperature,which is measured with the 3-omega sensors. Absence of modulation inrenal blood flow during pacing can indicate that ablation was successfuland enable physicians to determine the end point of the renaldenervation procedure.

In an example implementation, flow in a perfusion chamber can besystematically measured that provides programmable fluid volume velocityto test the sensitivity of a measurement system. Fluid flow rates can besystematically characterized at various ambient temperatures, ionicstrengths, and viscosities to test how heat flux, electro-osmosis(during electrical stimulation) and fluid boundary layer thicknessaffect flow. The perfusion chamber can be equipped with electricalsensors that allow concomitant testing of pacing and ablation.

An example method for performing a procedure is described in connectionwith FIG. 19. The example method includes disposing 1902 an exampledevice according to the principles described herein in proximity to atissue, the device including a catheter, at least one flow sensordisposed on a portion of the catheter, at least one component coupled tothe catheter to perform an ablation procedure on a portion of a tissueproximate to the catheter, and an assessment module coupled to the flowsensor to receive data indicative of at least one flow measurement fromthe at least one flow sensor and provide an indication of the efficacyof the ablation procedure based on the data indicative of at least oneflow measurement. The example method also includes applying 1904 theablation procedure to the surface of the tissue proximate to thecatheter and recording 1906 a measurement of the flow sensor to providean indication of the efficacy of the ablation procedure.

FIG. 20 shows an example architecture of an illustrative computer system2000 that can be employed to implement any of the systems and methodsdescribed herein. The computer system 2000 of FIG. 20 comprises one ormore processors 2020 communicatively coupled to memory 2025, one or morecommunications interfaces 2005, and one or more output devices 2010(e.g., one or more display units) and one or more input devices 2015.

In the computer system 2000 of FIG. 20, the memory 2025 may comprise anycomputer-readable storage media, and may store computer instructionssuch as processor-executable instructions for implementing the variousfunctionalities described herein for respective systems, as well as anydata relating thereto, generated thereby, or received via thecommunications interface(s) or input device(s). The processor(s) 2020shown in FIG. 20 may be used to execute instructions stored in thememory 2025 and, in so doing, also may read from or write to the memoryvarious information processed and or generated pursuant to execution ofthe instructions.

The example computer system 2000 also includes an assessment module2030. Assessment module comprises processor-executable instructions forperforming any of the methods described herein to, for example, providean indication of a flow rate, or to provide an indication of theefficacy of a procedure to disrupt nerves based on the measured valuesof flow rate. Processor 2020 can be used to execute theprocessor-executable instructions in connection with assessment module2030.

The processor 2020 of the computer system 2000 shown in FIG. 20 also maybe communicatively coupled to or control the communications interface(s)2005 to transmit or receive various information pursuant to execution ofinstructions. For example, the communications interface(s) 2005 may becoupled to a wired or wireless network, bus, or other communicationmeans and may therefore allow the computer system 2000 to transmitinformation to and/or receive information from other devices (e.g.,other computer systems). Communication interface(s) 2005 also may be incommunication with an external network 2035. In some implementations,the communications interface(s) may be configured (e.g., via varioushardware components or software components) to provide a website orapplications program (an App) on a handheld device as an access portalto at least some aspects of the computer system 2000. Non-limitingexamples of such hand-held devices are tablets, slates, smartphones,electronic readers, or other similar hand-held electronic devices.

The output devices 2010 of the computer system 2000 shown in FIG. 20 maybe provided, for example, to allow various information to be viewed orotherwise perceived in connection with execution of the instructions.The input device(s) 2015 may be provided, for example, to allow a userto make manual adjustments, make selections, enter data or various otherinformation, or interact in any of a variety of manners with theprocessor during execution of the instructions.

FIGS. 21A and 21B show the results of example measurement using anexample device according to the principles described herein. FIGS. 21Aand 21B show data from flow sensor measurements over a dynamic range offlow rates (from about 100 mL/min to about 600 mL/min) for a flow sensorstrategically tuned for renal hemodynamic. FIG. 21A shows measurementsmade for a 50 microAmps sensor. FIG. 21A shows measurements made for a20 microAmps sensor.

FIGS. 22A and 22B show the results of example use of an example deviceaccording to the principles described herein for use in performing anablative procedure at about 0.2 W to about 0.3 W of power usingelectrodes for different exposure times (5 sec, 10 sec, 15 sec, 30 sec,60 sec). The ablation electrodes are shown to generate lesions withinabout 5 seconds of contact with tissue, without charring. It is observedthat a lesion is generated once the electrodes are in contact with thetissue, soft contact was sufficient to generate lesions, without excesspressure being exerted.

An non-limiting example measurement implementation is described. Asystem according to the principles described herein can be used toprocess differential measurement. If one sensor is used, the bodytemperature of the subject would be taken into account as well as staticflow of the subject. This may require calibrations that may differ frompatient to patient, leading to less accurate results or may require thephysician to slow the procedure to take separate body temperature staticblood flow measurements in addition to the renal artery flowmeasurement.

Non-limiting examples of the innovations described in this disclosureinclude:

-   -   a) Expediting up the clinical procedure;    -   b) Providing more accurate results to the end point in therapy;        and    -   c) Reducing the amount of computation required.

In a non-limiting example, temperature sensing devices can be used incombination with a catheter to provide flow measurements. Electricalcircuits can be used to provide differential measurements. Thin,stretchable, flexible and/or conformal electronics can be used toprovide thin and conformal means to deploy the sensors described hereinon the balloon of the catheter. The flow sensing systems, device, andmethods described herein can be used for blood flow quantification andfor other types of fluid flows.

In different example implementations, the change in flow can be reportedto the clinician via direct values. The changes in flow can be used toshow the stage, the progress, or the degree of success, of a procedurebeing performed, such as but not limited to an ablation procedure, forexample, by indicating on a console or display device the procedurestatus. For example, a change in the flow rate above a defined value orthreshold, can be used to signal or trigger an action. In an example,the action can be the turning on of an indicator on the catheter device,or the display of an icon, numeric value or chart on a display. In anexample, the signal or trigger of the action can be used to provide theindication of the stage, the progress, or the degree of success of aprocedure.

According to the example systems, methods and devices herein, sensingtechnology onboard catheters are described that employ thin, conformalarrays of sensors that can deform with the curvilinear structure ofvarious balloon and spiral-shaped catheters. The ability to integrateconformal sensors along with silicon-based electronics on spiral-shapedextrusions and balloons facilitates, for the first time, ways tointegrate multimodal sensory elements, micro-light emitting diodes(μLEDs) and integrated circuit building blocks (i.e. amplifiers andlogic gates) onboard catheters, thereby optimizing sensing while at thesame time, not impacting the mechanical properties.

FIGS. 23A-23G illustrates examples of multi-electrode and ballooncatheter devices, according to the principles described herein. FIGS.23A-23G illustrates examples of multi-sensing element (includingmultielectrode) devices and catheter devices. The devices in FIGS.23A-23D include passive wires with polyimide-based encapsulation. Thewires are exposed in select areas, thus forming electrode contacts. Theelectrode array can include, for example, 64 electrodes. FIGS. 23E-23Gshow the balloon-based ablation catheters that can be used to applycryo-, laser-, and high intensity ultrasound-forms of therapy,respectively, when deployed proximate to tissue. Any system according tothe principles described herein can be implemented using any of thecatheters shown in FIGS. 23A-23G.

Other non-limiting examples of catheters that are applicable to thesystems, methods, and apparatus described herein include Mallecotcatheters, spiral coil catheter, mesh catheters, single-Rod catheters,compliant balloon-based catheters, non-compliant balloon-basedcatheters, lasso-shaped catheters, multispline catheters, dilatationballoon catheters, and angioplasty balloon catheters.

Examples of this kind of device are shown in FIGS. 24A-24D. Electrodes,flow sensors and μLEDs are able to withstand the significant mechanicalstrains caused by repetitive inflation and deflation cycles of theballoon by virtue of their nanomembrane form factor and the serpentineinterconnect geometries, which help to absorb mechanical strains. FIGS.24E and 24F highlight alternative forms of sensing—temperature sensors,electrodes and flow sensors on conformal substrates. The flow sensingand electrode elements are useful for RSDN catheters, because assessmentof blood flow can be achieved quickly, without the need for separatediagnostic devices.

In an example, 3-omega sensor arrays are used to measure thermalconductivity and other related thermal, mechanical and materialproperties that relate to thermal conductivity. To measure flow, thesensors are each positioned perpendicularly to the flow direction. Sucha configuration can be compatible with the design of a spiral shapedcatheter system. AC current is applied across each sensor and theresulting AC voltage is measured. This measured voltage decreasesmonotonically as flow rate increases and increases if the blood isstagnant or slows down. Computations of measured voltages according toany of the example devices herein can be calibrated using a perfusionchamber and the flow is assumed to follow the Hagen-Poiseuille equationand its respective assumptions. Measurements using 3-omega sensortechnology are versatile because they can be used to extract severalother physical parameters that may be relevant to clinicians. Thissensing modality can be used to serve as a viable platform forcatheters, e.g., that can be used to perform a renal denervation.

In an example, mechanical modeling of flow sensors and electrodes duringmechanical stress can be performed. Using modeling simulations, thedynamic material and mechanical properties can be characterized forconformal sensor arrays on balloon and spiral-shaped catheters thatexperience significant bending and twisting during operation. Thisincludes analytical and finite element modeling of the mechanics of flexelectronics affixed to balloon catheters. The strain distributionsobtained through analytical and computational modeling capture,quantitatively, the nature of deformations in the electronics layers.Characterization of the effective strain and displacement distributionsin the sensor islands and serpentine interconnects provide importantinsights into critical fracture strains and buckling phenomena. Suchcharacterization of conformal sensors can dramatically improve the waynanomembrane flow sensors and electrodes are designed and implemented onhighly deformable substrates (i.e. deflectable catheters). Furthermore,the approach holds promise for increasing the understanding of themechanical stresses involved during catheter deployment in vivo.

FIG. 25 shows non-limiting examples of flow sensors on rod-shapedcatheters that include “clover-shaped” flow sensors. The metalrectangles are electrodes on the catheter. In some of the examplecatheters of FIG. 25, the flow sensors include angioplasty balloons withablation electrodes (the circular pads). In the novel example systemsherein, the clover flow sensors are combined with the balloon electrodeson a single device.

According to the systems and methods described herein, ablationelectrodes can be embedded on angioplasty balloon along with theclover-shaped flow sensors on the proximal and distal sides of theballoon on the catheter extrusion. According to the novel systems andmethods herein, a multifunctional balloon catheter that has (i) array ofelectrodes is coupled with (ii) flow sensors embedded on the catheter'sshaft proximate to the balloon. In some examples, the balloon cathetermay include other sensors on the balloon, such as but not limited toLEDs, contact sensors, pressure sensors, biological activity sensors,and temperature sensors.

In an example implementation, the catheter with balloon is deployedproximate to the renal tissue (or other portion of the renal system) ina deflated state. For example, once the catheter is in the renal artery,fluid flow can be measured (including blood flow). Once captured, theballoon can be inflated and the ablation can be performed. Once theablation is completed, or at selected points during performance of theablation, the balloon can be deflated and flow is sensed again to seewhat changes are measured. In this example, an increase in flow can beused to serve as an indicator of a successful ablation procedure.

In another example implementation, the nerve can be paced and the flowcan be measured pre-ablation. The ablation cycle can be performed. Oncethe ablation is completed, or at selected points during performance ofthe ablation, the nerve can be paced and the flow can be measured again(including a post-ablation measurement). If the pacing is determined tocauses a change in flow, this can be used as an indicator that thenerves are still active. If the pacing does not cause a shift in flow,this can be used as an indicator that the nerves have been successfullydenervated. The flow sensors coupled with ablation electrodes accordingto the systems and methods described herein facilitate this novelanalysis and determination of clinical endpoint.

FIG. 26 shows a non-limiting example of flow sensors on a spiral-shapedcatheters. FIG. 27 shows a catheter with bipolar electrodes and metalinterconnects disposed on its surface.

Example design and fabrication are described for examples of 4 flowsensors, 4 pacing electrodes and 4 ablation electrodes all co-located onspiral-shaped catheters. A custom data acquisition system isimplemented, and the initial functionality of the flow sensors andelectrodes is tested by deploying them in flow perfusion chambers.Example combined functionalities of the flow sensors, pacing electrodesand ablation electrodes in the renal arteries of live porcine models arealso described. Spiral catheters containing the sensors and electrodesare used to measure blood flow during nerve stimulation immediately pre-and post renal ablation event. A comparative analysis is conducted of acatheter system's performance, ease of use, and procedure time relativeto other renal ablation devices being used in the clinical setting togain insight into how having a clinical endpoint in RSDN helps toimprove the overall procedure efficacy and safety.

Non-limiting examples of flow sensors, pacing and ablation electrodes onmultifunctional spiral catheter in perfusion apparatus is described.Constrained spaces in the renal artery can reduce the number of devicesthat can be positioned inside. As a result, it can be challenging todeploy multiple devices in such as a confined space as in the renalarteries. Multifunctional RSDN catheters are constructed with electrodeson spiral-shaped extrusions that are small enough to conform to therenal artery to enable electrical stimuli delivery without affectingmeasurements. Mechanically optimized nanomembrane electrodes areincorporated with 3-omega flow sensors that interface with the limitedspace of the renal artery. In an example, up to 8 electrodes (0.25×0.25mm²) and 4 (1×1 mm²) sensors are fabricated to measure renal blood flowpre- and post-ablation events. A data acquisition system (NationalInstruments Inc.) is implemented, coupled with an Electrical stimulatorconsole (Medtronic Inc.) to deliver the 5-10 W of energy to pace andablate the renal nerves. This power supply can be used to apply pacingenergy. Using this new system, fundamental limits of the ablation andpacing electrodes with in vitro tissue can be characterized. Inaddition, a custom perfusion chamber can be built to test the flowsensing capabilities. Taken together, these new designs,microfabrication approaches and measurements using in-vitro models canprovide insight into the optimal configuration of electrodes and flowsensors necessary determine changes in flow rate following renaldenervation.

Non-limiting example pacing and ablation electrodes on spiral catheterand test performance in vitro are described. Ultrathin geometries impartflexibility to otherwise rigid and brittle materials. Ultrathinconformal nanomembrane sensors (˜250 nm) embedded in thin polyimide andelastomeric substrates (˜50-100 μm) in neutral mechanical plane layoutsaccommodate significant mechanical durability with radii of curvatureless than about 1 mm. To achieve conformal sensors with such designs,arrays of electrodes can be formed on silicon. Lithographic processingand vertical trench wet-etching techniques yield isolated chiplets(˜0.25×0.25 mm², and ˜1-5 μm thick) that remain tethered to theunderlying wafer through ‘anchor’ structures. This process can be usedto yield electrodes that are referred to as ‘printable’, due to theirability to be removed and placed onto a target substrate with a soft,elastomeric stamp and transferred onto a spiral catheter. The attractivefeatures of this approach include: (1) ultrathin circuit layouts formechanical flexibility to conform to limited space in the renal artery,and (2) compatibility with other elements such as contact or flowsensors.

The utility of nanomembrane electrodes are tested be perform ablationmeasurements by driving RF energy (5-10 W) to show that renal nervesfibers can be ablated through arterial vessel. Histological assessmentis performed of the nerves pre- and post ablation cycles to testnanomembrane electrode array performance and to see if the surfaceproperties of the electrodes change over time (as a result of proteincoating and/or electromosis phenomena). Measurements performed in theheart and on excised muscle tissue yield promising results on bothpacing and ablation with this new class of nanomembrane electrodes.

A non-limiting example data acquisition system is described. Stimulationwaveforms in the form of rectified triangular pulses with fixedamplitude of 10-20 V and 100-150 ms durations can be delivered throughthe pacing electrodes using instructions programmed into machinereadable instructions. The waveform patterns are chosen strategically toinduce renal nerve activity and to give rise to vasoconstriction orchanges in local blood flow. The data acquisition system includes threemodules to measure blood flow, induce nerve stimulation, and deliverablation energy. The data from any of these modules can be transmittedto the assessment module to perform an assessment of efficacy asdescribed in connection with any of the examples described herein. ANational Instruments Inc. PXI-6289 (a multifunction M Series dataacquisition (DAQ) system), controlled with custom machine readableinstructions (including in LABVIEW™ software), controls voltages acrossthe sensors.

Non-limiting example flow sensing, pacing and ablation usingmultifunctional spiral catheters in live animal models are described.Multifunctional balloon and spiral shaped catheter described in section1 above are applied to flow sensing and ablation measurements in liveanimal models. Balloon catheters can be used. In an example, ballooncatheters may have larger profiles that can affect flow. In anon-limiting example, to minimize effects of the catheter on blood flow,spiral-shaped catheters can be used instead of balloons. Flow can bemeasured upon initial deployment in the renal arteries over the courseof a few minutes to determine the initial average flow rate. Onceestablished, pacing can ensue and flow can be monitored concurrently. A20-30% reduction in flow can be expected during this step if the renalnerves are functioning properly. Once this initial calibration iscompleted, the same set of procedures can be run following renalablation cycles. It is possible that the renal blood flow may shift to adifferent baseline than in the initial measurement. In an example, thisis not used as an indicator of successful ablation. If ablation issuccessful, there can be an interpretable effect that can be apparentduring pacing. That is, there may be little shift in flow during pacingbecause the vasoconstriction properties of the nerves can bedysfunctional, which can serve as the clinical endpoint of theprocedure.

In an example, an example method for determining renal denervationendpoint when blood pressure and flow are modulated with nitroglycerineis described. To determine how changes in flow can be assessed with thesensors described herein, variations in blood flow caused bynitroglycerine lead to changes in blood pressure and renal blood flowrates before and after ablation can be monitored. Systemic injections ofnitroglycerine can cause shifts in blood pressure that can give rise tochanges in renal blood flow. Injections of nitroglycerine also can bemonitored to determine an affect on blood flow pre-pacing and againfollowing pacing.

In an example, leakage currents and encapsulation are described.Conformal flow sensor arrays can be fabricated using a multi-layerprocess, which has a thin layer polyimide as the encapsulating layer.Horizontal and vertical interconnect layers are insulated using thisthin layer of polyimide. In an example system, leakage currents mayescape and lead to noisy recordings, bubble formation in the fluid, orsensor deterioration over time. In an example, to prevent leakagecurrents in these systems, additional polymeric encapsulation (UVcurable polyurethanes or parylenes) can be coated over the sensors,creating an additional ˜10 m encapsulating layer to withstand currentleakage effects. Over the course of a few hours (the extent of RSDNprocedures), leakage currents may be manageable with polyurethane,parylene and UV curable encapsulation strategies.

Data visualization and signal fidelity is described. Data acquisitionsystems developed for recording flow, pacing and ablation may not beprovided in a single module. The visualization of the measurementsrecordings and stimuli application may require feedback from multiplephysicians. Interpretation of the flow data in real time can bechallenging. A first generation data acquisition system is described formeasuring and displaying flow. In an example, the user interface can beconfigured to be presented on the same LABVIEW™ display as the controlsfor pacing and ablation, thereby providing all of the catheter controlfeatures on a single console. This system architecture may be wellsuited for a product development implementation.

Renal nerve stimulation is described. In some examples, the nerve pacingelectrodes may lose contact with the arterial vessel wall. Thisvariability in good contact may cause poor denervation results. Tocounter this effect, x-ray imaging and electrode impedance recordingscan be monitored to restore proper contact with the vessel wall.

Also provided herein is a user interface that can be used during aprocedure to monitor the progress of the procedure and/or to provide anindication of an endpoint of the procedure. The user interface can beprovided using an apparatus for displaying representations of theparameters of an inflatable body and/or expandable body disposedproximate to a portion of a tissue that is being treated. According tothe principles herein, the inflatable body and/or expandable body caninclude a plurality of sensors coupled to at least a portion of theinflatable body and/or expandable body. The apparatus can include a userinterface, at least one memory to store processor-executableinstructions, and at least one processing unit coupled to the at leastone memory. Upon execution of the processor-executable instructions, theat least one processing unit controls the user interface to display atleast one representation of the parameters of the inflatable body and/orexpandable body.

FIGS. 28A and 28B show non-limiting examples of the types ofrepresentation of the parameters of the inflatable body and/orexpandable body that can be shown on a display. FIG. 28A shows anexample first representation of the state of the inflatable body and/orexpandable body. The inflatable body and/or expandable body can be shownusing a first form indicator 2802 to indicate that it is in aninflated/expanded state, or using a second form indicator 2804 toindicate that it is in a deflated/collapsed. FIG. 28B shows examples ofthe types of representations that can be used to indicate the state ofat least one sensor of the plurality of sensors coupled to theinflatable body and/or expandable body. One or more of the sensors canbe represented using a first activation indicator 2852 to indicate thatrespective sensor measures a signal below a threshold value, or using asecond activation indicator 2854 to indicate that respective sensormeasures a signal above or about equal to the threshold value.

In an example, the first activation indicator 2852 and the secondactivation indicator 2854 can be used to indicate a state of contact ofa portion of the inflatable body and/or expandable body with a tissue Asignal below the threshold value can be interpreted as indicating thatthe at least one sensor is not in contact with a portion of the tissue,and a signal above or about equal to the threshold value indicates thatthe at least one sensor is in contact with a portion of the tissue.

In an example, the first activation indicator and the second activationindicator can be displayed as binary visual representations, e.g.,ON/OFF or other binary indication.

In an example, the first activation indicator and the second activationindicator can be displayed as quantitative visual representations thatcorrespond to a magnitude of the signal. For example, as shown in FIG.28C, the display can show a feature (such as an arrow or bar) thatchanges to indicate a magnitude of a signal to a sensor. The example ofFIG. 28C shows values for “contact” or “no contact”. In other examples,the features in the display could be used to indicate relativemagnitudes of any other parameter measured using a sensor. In anexample, a graphical plot, such as shown in FIG. 28D also can be used toindicate the magnitude of the signal.

In an example, the sensor(s) may be flow sensor(s), and the firstactivation indicator and the second activation indicator can bedisplayed as quantitative visual representations that indicate themagnitude of parameters such as but not limited to an instantaneousvelocity, a volumetric flow, or a vascular resistance of the measuredfluid flow rate at each sensor.

In an example, the first form indicator and the second form indicatorcan be displayed as color-coded symbols. Each color-coded symbol can beused to indicative of a range of values of the magnitudes of the signal.For example, green can be used to indicate a low range of values below afirst threshold, yellow can be used to indicate a signal falling in amid-range of values up to a second threshold, and red can be used toindicate a signal falling in a high range of values above the secondthreshold.

In an example, the first form indicator and the second form indicatorcould further be used to provide an indication of a spatial location ofthe corresponding at least one sensor relative to the inflatable bodyand/or expandable body. For example, the indicators 2852 and 2854 can beused to indicate the spatial location of the sensor that is activated.

In an example, the user interface can be configured to cause display ofthe representation of the inflatable body and/or expandable body and therepresentation of the state of activation of the sensor(s) in a stagedprocess. No representation of the state of activation of the sensor(s)would be displayed while the representation of the inflatable bodyand/or expandable body is the first form indicator (indicating adeflated/collapsed state). The representations of the state ofactivation of the sensor(s) would be displayed once the representationof the inflatable body and/or expandable body is the second formindicator (indicating an inflated/expanded state). That is, therepresentations of the state of activation of the sensors may not beallowed to be display, until the inflatable body and/or expandable bodyis somewhat inflated/expanded (even if not fully inflated or expanded).

In an example, the user interface can be configured to displayinstructions to a practitioner (including a physician) at various stagesof the procedure being performed. The example, the display can beconfigured to indicate when an endpoint of the procedure has beenreached. If the procedure has not reached an endpoint, the display canbe configured to display instructions to indicate to the practitioner tocontinue the procedure or modify the procedure (e.g., to move thecatheter, guidewire or other elongated body or the inflatable bodyand/or expandable body, or to re-apply the treatment (e.g., theablation). The user interface also can be configured to display of anindication of at least one stage of the procedure being performed on theportion of the tissue.

In an example shown in FIG. 29, the user interface can be used todisplay vascular resistance value(s) in numerical form and/or as a graphvs. time. The user interface also can be used to display data indicativeof parameters such as but not limited to the systolic slope, thepulsatile flow, and the pulsatile pressure. The user interface can beconfigured to display values indicative of the instantaneous/volumetricflow in a short-time duration graph that shows granular flow readings.The user interface can be configured to display values of theinstantaneous/volumetric flow in a long time-scale graph, e.g., over thecourse of the duration of the procedure (e.g., an hour-long procedure),to discern changes pre- and post-treatment (such as but not limited tothe ablation.

While various inventive embodiments have been described and illustratedherein, those of ordinary skill in the art will readily envision avariety of other means and/or structures for performing the functionand/or obtaining the results and/or one or more of the advantagesdescribed herein, and each of such variations and/or modifications isdeemed to be within the scope of the inventive embodiments describedherein. More generally, those skilled in the art will readily appreciatethat all parameters, dimensions, materials, and configurations describedherein are meant to be examples and that the actual parameters,dimensions, materials, and/or configurations will depend upon thespecific application or applications for which the inventive teachingsis/are used. Those skilled in the art will recognize, or be able toascertain using no more than routine experimentation, many equivalentsto the specific inventive embodiments described herein. It is,therefore, to be understood that the foregoing embodiments are presentedby way of example only and that inventive embodiments may be practicedotherwise than as specifically described. Inventive embodiments of thepresent disclosure are directed to each individual feature, system,article, material, kit, and/or method described herein. In addition, anycombination of two or more such features, systems, articles, materials,kits, and/or methods, if such features, systems, articles, materials,kits, and/or methods are not mutually inconsistent, is included withinthe inventive scope of the present disclosure.

The above-described embodiments of the invention may be implemented inany of numerous ways. For example, some embodiments may be implementedusing hardware, software or a combination thereof. When any aspect of anembodiment is implemented at least in part in software, the softwarecode may be executed on any suitable processor or collection ofprocessors, whether provided in a single device or computer ordistributed among multiple devices/computers.

Also, the technology described herein may be embodied as a method, ofwhich at least one example has been provided. The acts performed as partof the method may be ordered in any suitable way. Accordingly,embodiments may be constructed in which acts are performed in an orderdifferent than illustrated, which may include performing some actssimultaneously, even though shown as sequential acts in illustrativeembodiments.

All definitions, as defined and used herein, should be understood tocontrol over dictionary definitions, definitions in documentsincorporated by reference, and/or ordinary meanings of the definedterms.

The indefinite articles “a” and “an,” as used herein in thespecification, unless clearly indicated to the contrary, should beunderstood to mean “at least one.”

The phrase “and/or,” as used herein in the specification, should beunderstood to mean “either or both” of the elements so conjoined, i.e.,elements that are conjunctively present in some cases and disjunctivelypresent in other cases. Multiple elements listed with “and/or” should beconstrued in the same fashion, i.e., “one or more” of the elements soconjoined. Other elements may optionally be present other than theelements specifically identified by the “and/or” clause, whether relatedor unrelated to those elements specifically identified. Thus, as anon-limiting example, a reference to “A and/or B”, when used inconjunction with open-ended language such as “comprising” can refer, inone embodiment, to A only (optionally including elements other than B);in another embodiment, to B only (optionally including elements otherthan A); in yet another embodiment, to both A and B (optionallyincluding other elements); etc.

As used herein in the specification, “or” should be understood to havethe same meaning as “and/or” as defined above. For example, whenseparating items in a list, “or” or “and/or” shall be interpreted asbeing inclusive, i.e., the inclusion of at least one, but also includingmore than one, of a number or list of elements, and, optionally,additional unlisted items. Only terms clearly indicated to the contrary,such as “only one of” or “exactly one of,” or “consisting of,” willrefer to the inclusion of exactly one element of a number or list ofelements. In general, the term “or” as used herein shall only beinterpreted as indicating exclusive alternatives (i.e. “one or the otherbut not both”) when preceded by terms of exclusivity, such as “either,”“one of,” “only one of,” or “exactly one of.”

As used herein in the specification, the phrase “at least one,” inreference to a list of one or more elements, should be understood tomean at least one element selected from any one or more of the elementsin the list of elements, but not necessarily including at least one ofeach and every element specifically listed within the list of elementsand not excluding any combinations of elements in the list of elements.This definition also allows that elements may optionally be presentother than the elements specifically identified within the list ofelements to which the phrase “at least one” refers, whether related orunrelated to those elements specifically identified. Thus, as anon-limiting example, “at least one of A, and B” (or, equivalently, “atleast one of A or B,” or, equivalently “at least one of A and/or B”) canrefer, in one embodiment, to at least one, optionally including morethan one, A, with no B present (and optionally including elements otherthan B); in another embodiment, to at least one, optionally includingmore than one, B, with no A present (and optionally including elementsother than A); in yet another embodiment, to at least one, optionallyincluding more than one, A, and at least one, optionally including morethan one, B (and optionally including other elements); etc.

What is claimed is:
 1. A device for determining a flow rate of a fluidproximate to a portion of a tissue, comprising: an elongated memberhaving a proximal portion and a distal portion; a flow sensor disposedproximate to the distal portion of the elongated member, the flow sensorcomprising: at least one temperature sensor; and at least one heatingelement to heat an area proximate to the elongated member, at least aportion of the at least one heating element forming a cavity, wherein:at least a portion of the at least one temperature sensor is housed in aportion of the cavity; and a temperature measurement of the temperaturesensor provides a first indication of a flow rate of the fluid proximateto the flow sensor.
 2. The device of claim 1, further comprising aninflatable and/or expandable body coupled to a portion of the elongatedmember and having a proximal portion and a distal portion, wherein thedistal portion of the inflatable and/or expandable body is disposedproximate to the flow sensor.
 3. The device of claim 2, furthercomprising an electronic circuit coupled with the inflatable and/orexpandable body, wherein the electronic circuit comprises at least onestretchable interconnect, and wherein the electronic circuit isstretchable and conformable such that the electronic circuitaccommodates an expansion of the inflatable and/or expandable body. 4.The device of claim 3, wherein the electronic circuit further comprisesat least one passive electronic component and/or at least one activeelectronic component, and wherein the at least one stretchableinterconnect electrically couples at least two electronic components ofthe electronic circuit.
 5. The device of claim 3, wherein the electroniccircuit further comprises a plurality of electrodes, and wherein atleast one electrode of the plurality of electrodes is a radiofrequencyelectrode to deliver a radiofrequency energy to a surface proximate tothe radiofrequency electrode.
 6. The device of claim 3, wherein theelectronic circuit comprises at least one ablative element.
 7. Thedevice of claim 1, wherein the device is adapted for performing aprocedure on the portion of tissue, and wherein the procedure is adenervation procedure or a nerve stimulation procedure.
 8. The device ofclaim 7, wherein the procedure is a carotid sinus denervation, a carotidbody disruption, a vagus nerve stimulation, a pulmonary arterydenervation, a celiac ganglion disruption, a bladder trigone ablation,or a renal denervation.
 9. The device of claim 1, wherein thetemperature sensor is a thermistor or a thermocouple.
 10. The device ofclaim 1, wherein the elongated member is a catheter or a guide wire. 11.The device of claim 1, further comprising a reference temperature sensordisposed on a proximal portion of the elongated member.
 12. The deviceof claim 11, wherein a comparison of a temperature measurement of thereference temperature sensor to a measurement of the flow sensorprovides a second indication of a flow rate of the fluid.
 13. The deviceof claim 1, wherein the at least one flow sensor is a plurality of flowsensors.
 14. The device of claim 1, wherein the fluid is blood, andwherein the first indication of the flow rate of the fluid is indicativeof a hemodynamic property of the fluid.
 15. The device of claim 1,further comprising at least one component adapted to perform an ablativeprocedure.
 16. The device of claim 15, further comprising at least onepacing electrode disposed on the inflatable and/or expandable body todeliver an electrical stimulation to a portion of the tissue proximateto the pacing electrode.
 17. The device of claim 16, wherein theelectrical stimulation is applied to the portion of the tissue prior toperforming the ablation procedure.
 18. The device of claim 1, whereinthe operation of the heating element and the temperature sensor arecoupled to provide a measure of a change in temperature caused by achange in the flow rate of the fluid.
 19. The device of claim 1, whereinthe flow sensor is encapsulated in a thermally-conductive encapsulant.20. The device of claim 1, wherein the at least one heating elementcomprises a coiled resistive wire, and wherein a hollow portion of thecoiled resistive wire forms the cavity.
 21. The device of claim 1,wherein the at least one heating element comprises a thin-film patternedresistive element, and wherein the at least one heating element isformed in a substantially cylindrical conformation including the cavity.22. The device of claim 21, wherein the thin-film patterned resistiveelement comprises a pattern of resistive elements disposed on astretchable and/or flexible substrate.
 23. The device of claim 22,wherein the resistive elements are formed in a linear pattern, aserpentine pattern, a boustrophedonic pattern, a zig-zag pattern, a wavypattern, a polygonal pattern, or a substantially circular pattern.